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HELLO EVERYONE. WELCOME
TO

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THE NIH DNA REPAIR INTEREST

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GROUP VIDEO CONFERENCE. TODAY WE

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ARE HONORED TO HAVE A PROFESSOR

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ALLEN LEHMANN. PROFESSOR LEHMANN

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IS RESEARCH PROFESSOR FOR

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MOLECULAR GENETICS, GENOME

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DAMAGE AND DISABILITY CENTER

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UNIVERSITY OF SUSSEX. HE

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RECEIVED HIS BACHELORS DEGREE IN

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CAME BRIDGE AND Ph.D. DEGREE

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IN LONDON. HE -- DR. LEHMANN

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HAVE LOT OF HONORS AND AWARDS,

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INCLUDING THE FELLOWS OF ACADEMY

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OF MEDICAL SCIENCES AND AND

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FEDERAL SOCIETY OF BIOLOGY. HE

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HAS ALSO BEEN AWARDED THE EU

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PRIZE AND FIRST SOLO PRIZES OF

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THE EUROPEAN ENVIRONMENTAL

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SOCIETY. SO WITHOUT FURTHER

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ADIEU, WE WILL HAVE THE STAGE TO

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PROFESSOR LEHMANN FOR THE

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AUDIENCE, PLEASE IF YOU HAVE ANY

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QUESTIONS PLEASE TYPE IT IN THE

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CHAT BOX AND WE WILL ELABORATE

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AFTER THE TALK. THANK YOU.

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PROFESSOR LEHMANN.

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>> OKAY. THANK YOU VERY
MUCH FOR

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THE INTRODUCTION. I'M GOING TO

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DIVIDE THE TALK INTO TWO REALLY

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UNCONNECTED PARTS. THE FIRST

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PART WILL BE A HISTORY OF

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TRANSLESION SYNTHESIS, FROM THE

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YEARS 1968 TO 1999. AND THEN FOR

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THE REST OF THE TALK I'M GOING

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TO BE TELLING YOU ABOUT THE

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MULTI-DISCIPLINARY CLINIC XP

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SYNDROME TTD IN THE UK AND FOCUS

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ON TWO CASES WHICH WILL BE OF

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PARTICULAR INTEREST. SO TO START

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WITH TRANSLATION SYNTHESIS, I'M

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GOING BACK TO ANCIENT HISTORY

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FROM 1968 TO 1980. 1968 WAS A

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SEMINOLE YEAR IN THE DNA REPAIR

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FIELD FOR TWO MAJOR DISCOVERIES.

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THE FIRST ONE WAS BY JAMES

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CLEAVER, SHARING XP CELLS INTO

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MUTAGEN (INAUDIBLE) SO CLEAVER

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IN 1968 PUBLISHED A PAPER

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SHOWING FIBROBLASTS FROM XP

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PATIENTS AFTER UV. THE

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EXPERIMENT WAS TO TAKE NORMAL OR

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XP CELLS UV IRRADIATE THEM AND

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INCUBATE THEM IN THE HEAVY

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ANALOG PROXY URIDINE AND

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SEPARATE DNA ON THE BASIS OF

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ENTITY ON THE SODIUM CHLORIDE

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GRADIENT. I WON'T GO INTO

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DETAILS OF THE -- HOW THE

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EXPERIMENT WORKS, ALL YOU NEED

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TO KNOW IF YOU SEE A SOLID BAND

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THIS POSITION HERE YOU HAVE

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REPAIR SYNTHESIS. NORMAL CELLS

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NO UV, NO EVIDENCE OF ANY

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REPAIR. LOW DOSE UV YOU BEGIN TO

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SEE HINT OF A PEAK HERE THEN

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HIGHER DOSE UV, A CLEAR CLEAR

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PEAK HERE INDICATING YOU HAVE

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REPAIR SYNTHESIS IN NORMAL HUMAN

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FIBROBLASTS. CONTRAST THIS WITH

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XP FIBROBLASTS WHERE ZERO LOW

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DOSE OR HIGH DOSE OF UV YOU FIND

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NO TRACE OF REPAIR SYNTHESIS. SO

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THIS IS THE FIRST EVIDENCE THAT

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XP CELLS ARE DEFICIENT IN WHAT

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WE NOW CALL NER. THE SECOND

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DISCOVERY WAS POST REPLICATION

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REPAIR, (INAUDIBLE) IN YALE

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PUBLISHED IN IN THE SAME YEAR.

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SO THE EXPERIMENT HERE YOU TAKE

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E. COLI CELLS, UV IRRADIATE

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THEM, TIME DEAN AND FOLLOW WITH

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A CHASE OF COLD THYMADINE NOW

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SEPARATION IS ON THE BASIS OF

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SIZE. (INAUDIBLE) RIGHT TO LEFT

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SO BIG DNA ON THE LEFT, SMALL

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DNA ON THE RIGHT. IN

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UNIRRADIATED CELLS, THE PULSE

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LABEL SHIELDED ALL THE DNA WAS

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BIG SO NEARLY SYNTHESIZED DNA

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WAS PRETTY BIG SIZE. HOWEVER,

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AFTER CELLS FOR UV IRRADIATED

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THE NEWLY SYNTHESIZED DNA WAS

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SMALLER AS YOU CAN SEE HERE.

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THEN IF YOU INCUBATE FURTHER THE

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SMALL DNA BECAME BIG. THEY

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PROPOSE WHAT WAS HAPPENING IS

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DNA WITH PHOTO PRODUCT IN THE

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NEWLY SYNTHESIZED DNA, GAPS WERE

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LEFT OPPOSITE THE (INAUDIBLE).

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AND THE TRACE INDICATED THE GAPS

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WERE SOMEHOW SEALED BUT AT TIME

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NO INDICATION WHAT THE MECHANISM

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MIGHT BE. TWO OR THREE YEARS

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LATER PUBLISHED ANOTHER PAPER

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THEY SHOWED THE GAPS WERE FILLED

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IN BY (INAUDIBLE) IN E. COLI. SO

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HERE IS DAMAGE WITH A GAP

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OPPOSITE IT AND DNA THAT SHOULD

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GO IN HERE, THIS IS THE SAME

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SEQUENCE AS IN THE PARENTAL DNA

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OF THE SISTER DUPLEX SO

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SUGGESTED AND PROVIDED EVIDENCE

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THAT THERE WERE EXCHANGES

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WHEREBY PARENTAL DNA AND NEWLY

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SYNTHESIZED GOT SWAPPED INTO

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NEWLY SYNTHESIZED DNA, THERE BY

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REGAINING GENETIC INFORMATION. 

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SO IN 1972 I WAS DOING -- IN

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1970, 71 I WAS DOING A POST-DOC

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IN (INAUDIBLE) LAB AND I WANTED

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TO SEE IF SIMILAR THINGS

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HAPPENED IN MAMMALIAN CELLS.

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THAT TIME I WAS USING MOUSE

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CELLS. SO THIS IS THE EXPERIMENT

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THAT I DID. HERE IS TWO REPLY

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CONS THE SOLID LINES HERE ARE

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PARENTAL DNA, THIS IS NEWLY

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SYNTHESIZED DNA, X REPRESENTS

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PHOTO PROBLEMS AND HERE ARE DNA

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THAT IS LABELED WITH RADIATED

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THIMADINE AND GAPS WERE LEFT

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OPPOSITE THE PHOTO PRODUCTS JUST

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LIKE IN E. COLI. SUBSEQUENT STEP

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WAS TO INCUBATE WITH

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DEOXIURIDINE. SO THERE ARE NOW

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TWO POSSIBILITIES. IF THESE GAPS

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ARE FILLED IN BY EXCHANGE AS IN

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E. COLI THEN MATERIAL THAT GOES

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IN HERE WOULD BE PARENTAL DNA

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AND WOULD NOT CONTAIN THERMO

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DEOXIURIDINE. ON THE OTHER HAND

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IF GAPS WERE FILLED BY WHAT WE

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NOW CALL SYNTHESIS, THERE WOULD

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BE FILLED IN WITH DEOXIURIDINE

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INDICATED BY THESE BLACK BLOCKS 

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SO THE (INAUDIBLE) LAB WAS

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MAKING USE OF TECHNOLOGY AT THAT

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TIME WHEREBY DEOXIURIDINE

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SUBSTITUTED DNA IF YOU

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IRRADIATED IT AT 313 NANOMETERS

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HIGH DOSE, THAT PRODUCED BREAKS

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IN BROMODEOXIURIDINE SUBSTITUTED

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DNA BUT NOT IN DNA THAT CAME

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WITH THIMADINE LABELED SO IN

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THIS CASE ON THIS SCENARIO 313

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NANOMETER IRRADIATION WOULD NOT

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BREAK THIS DNA BECAUSE IT WAS

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THIMADINE LABELED THE PARENTAL

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DNA FROM THE SISTER DUPLEX. ON

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THE OTHER HAND TRANSLATED

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SYNTHESIS IRRADIATION WOULD GROW

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WITH 313 NANOMETERS TO REFORM

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GAPS INDICATED HERE. INDEED WITH

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WHAT I FOUND, IT APPEARED LIKE

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GAPS WERE BEING FILLED IN BY

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TRANSLESION SYNTHESIS AND NOT

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LIKE SISTER TRANSEXCHANGES FOUND

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IN E. COLI. AGAIN WE HAD NO

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INFORMATION AS TO HOW THIS

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TRANSLESION SYNTHESIS MIGHT TAKE

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PLACPLACE. I DO RECALL IN 1971

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SUGGESTING THERE MIGHT BE A DNA

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POLYMERASE THAT COULD SYNTHESIZE

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ACROSS THAT BUT THAT WAS

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REGARDED AS RATHER A LUNATIC

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IDEA UNFORTUNATELY I NEVER

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PUBLISHED IT SO I CAN'T GET ANY

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CREDIT FOR IT.  MOVING ON ABOUT

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THE SAME TIME, DISCOVERY OF XP

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VARIANTS BY THE LAB OF JAY

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ROBINS OVER THERE WITH NIH. THIS

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IS TAKEN FROM ROBINS AND KRAMER

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REVIEW IN 1974. WHAT THEY ARE

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SHOWING HERE IS THIS XP VARIANT

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PATIENT HAD VERY SIMILAR

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CLINICAL FEATURES TO THE XPC

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PATIENT INDICATED NEXT DOOR. IN

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FACT HAD MORE THAN 100 SKIN

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CANCERS AND DIED AT AGE 27. BUT

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IN CONTRAST TO THE XPC, THESE XP

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CELLS HAD NORMAL UDS. SO WHAT

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WAS GOING ON HERE? SO NOW

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UNIVERSITY OF SAW SEX I SET UP

195
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MY OWN LAB AND -- SUSSEX. XP

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VARIANTS WE WANTED TO SEE IF

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THEY WERE IN THE REPAIR PROCESS.

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SO THE EXPERIMENT WAS TO UV

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IRRADIATE POST LABEL RADIATED

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THIMADINE AND CHASE AGAIN WITH

201
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OR CUT CAFFEINE SO THEY ARE

202
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SHOWN TO SYNTHESIZE CERTAIN

203
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CELLS TO IRRADIATION BUT

204
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COULDN'T THINK OF ANYTHING ELSE

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TO DO CHUCKING CAFFEINE TO SEE

206
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CHAPS. THIS PROVED TO BE

207
00:09:39,485 --> 00:09:41,454
PROFITABLE ON THIS OCCASION.

208
00:09:41,454 --> 00:09:44,591
THIS IS AN ALKALINE SUCROSE

209
00:09:44,591 --> 00:09:46,059
GRADIENT, SODIUM FROM RIGHT TO

210
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LEFT, BIG DNA ON THE LEFT. IN

211
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NORMAL CELLS WE FOUND THE POST

212
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LABEL DNA AT THE UV IRRADIATION

213
00:09:52,065 --> 00:09:55,702
WAS SPREAD ACROSS THE GRADIENT.

214
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DISTRIBUTION OF DIFFERENT SIZES.

215
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WHEN WE INCUBATED IN THE CHASE,

216
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ALL THE DNA BECAME BIG AS YOU

217
00:10:01,040 --> 00:10:05,445
CAN SEE BY THE SOLID LINES HERE.

218
00:10:05,445 --> 00:10:07,480
ADDING CAFFEINE INDICATED BY THE

219
00:10:07,480 --> 00:10:08,448
THATCHED LINES HAVE NO EFFECT

220
00:10:08,448 --> 00:10:11,551
WHATSOEVER. CONTRAST THAT WITH

221
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THE XP VARIANT CELL LINE DOWN AT

222
00:10:14,621 --> 00:10:17,924
THE BOTTOM HERE. WE SHOW NEWLY

223
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SYNTHESIZED DNA AND NEWLY

224
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IRRADIATED CELLS MUCH SMALLER

225
00:10:20,627 --> 00:10:23,496
THAN NORMAL CELLS. FURTHER

226
00:10:23,496 --> 00:10:25,965
INCUBATION IT SLOWLY GOT BIGGER

227
00:10:25,965 --> 00:10:28,401
AND PUTTING IN CAFFEINE HERE HAD

228
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DIRECT EFFECT SMALL EFFECT IN

229
00:10:30,069 --> 00:10:32,739
THE PULSE BUT COMPLETELY

230
00:10:32,739 --> 00:10:33,773
INHIBITED CONVERSION OF LOW TO

231
00:10:33,773 --> 00:10:37,176
HIGH MOLECULAR DNA SHOWING THE

232
00:10:37,176 --> 00:10:40,179
VARIANTS HAVE A DEFECT IN WHAT

233
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WAS CALLED POST REPLICATION

234
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REPAIR. COUPLE OF YEARS LATER

235
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VERONICA MARS GROUP LOOKED AT

236
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THE UV OF XP VARIANTS. CELL

237
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KILLING FUNCTION OF UV NORMAL

238
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LINE AND XP VARIANT LINE, NOT

239
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PARTICULARLY SENSITIVE COMPARED

240
00:11:01,434 --> 00:11:04,003
TO DEFECTIVE XPs WHICH GIVE A

241
00:11:04,003 --> 00:11:06,673
LINE HERE. HOWEVER, IF THEY

242
00:11:06,673 --> 00:11:10,743
LOOKED AT MUTABILITY HERE IS

243
00:11:10,743 --> 00:11:14,847
NORMAL UV MUTABILITY AND VARYING

244
00:11:14,847 --> 00:11:17,083
LEVEL OF MUTABILITY AND THEY ARE

245
00:11:17,083 --> 00:11:19,419
DEFECTIVE XP. SO HERE WE HAVE A

246
00:11:19,419 --> 00:11:21,521
VERY NICE CORRELATION BETWEEN

247
00:11:21,521 --> 00:11:29,095
THE UV HYPERMUTABILITY AND THE

248
00:11:29,095 --> 00:11:30,964
SUSCEPTIBILITY TO INDUCE --

249
00:11:30,964 --> 00:11:36,502
SUNLIGHT INDUCED SKIN CANCERS. 

250
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SO VERY PRODUCTIVE PERIOD IN

251
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THIS AREA IN THE 19TH, LATE

252
00:11:40,740 --> 00:11:43,910
1960s AND 1970s BUT THEN IN

253
00:11:43,910 --> 00:11:46,913
1980ESS WE ENTERED THE DARK

254
00:11:46,913 --> 00:11:48,247
AGES, NOTHING MUCH HAPPENED OVER

255
00:11:48,247 --> 00:11:51,551
THIS PERIOD IN THIS AREA OF POST

256
00:11:51,551 --> 00:11:52,819
REPLICATION REPAIR TRANSLESION

257
00:11:52,819 --> 00:11:56,889
SYNTHESIS. NOW WE HAVE TO GO

258
00:11:56,889 --> 00:12:02,295
BACK A FEW YEARS AND LOOK AT THE

259
00:12:02,295 --> 00:12:05,164
ROLE OF MECHANISM OF UV

260
00:12:05,164 --> 00:12:08,901
MUTAGENESIS IN E. COLI. SO THE

261
00:12:08,901 --> 00:12:10,570
UNUC AND D GENES SHOWN REQUIRED

262
00:12:10,570 --> 00:12:13,473
FOR THE UV MUTAGENESIS IN E.

263
00:12:13,473 --> 00:12:15,441
COLI AS PART OF THE SOS

264
00:12:15,441 --> 00:12:17,710
RESPONSE. IN THE 1980s A90s

265
00:12:17,710 --> 00:12:19,178
THE ROLE WAS THOUGHT TO BE

266
00:12:19,178 --> 00:12:22,382
LOWERING THE STRINGENCY OF POLL

267
00:12:22,382 --> 00:12:25,818
3 TO ENABLE IT TO CARRY OUT

268
00:12:25,818 --> 00:12:27,687
TRANSLESION SYNTHESIS. SHOWING

269
00:12:27,687 --> 00:12:30,123
YOU THIS PICTURE TWO IMPORTANT

270
00:12:30,123 --> 00:12:32,692
PEOPLE INVOLVED IN THIS WORK.

271
00:12:32,692 --> 00:12:34,560
THIS IS BEN BRIDGES HERE, THIS

272
00:12:34,560 --> 00:12:36,229
HANDS SOME YOUNG FELLOW I THINK

273
00:12:36,229 --> 00:12:39,999
IS ONLINE TODAY, THAT IS ROGER

274
00:12:39,999 --> 00:12:42,668
WOODGATE. WHEN HE WAS DOING A

275
00:12:42,668 --> 00:12:46,506
Ph.D. WITH BRAIN AT THE TIME. 

276
00:12:46,506 --> 00:12:48,408
SO THEN MOVING ON TO THE

277
00:12:48,408 --> 00:12:51,377
BIOCHEMISTRY OF UMUC AND D WHAT

278
00:12:51,377 --> 00:12:54,380
DO THEY DO? FIRST BIT OF

279
00:12:54,380 --> 00:12:55,515
INFORMATION I WANT TO GIVE YOU

280
00:12:55,515 --> 00:12:58,184
IS THEY FOUND SOS INDUCTION

281
00:12:58,184 --> 00:13:01,154
RESULTS IN CLEAVAGE OF END

282
00:13:01,154 --> 00:13:03,389
TERMINAL 24 AMINO ACID THE UMUD

283
00:13:03,389 --> 00:13:04,657
PROTEIN. THESE THREE LABS SHOWED

284
00:13:04,657 --> 00:13:09,762
THAT. BEN ROGERS WITH PATRICK

285
00:13:09,762 --> 00:13:11,364
SHOWED THERE WAS COMPLEX FORMED

286
00:13:11,364 --> 00:13:14,534
OF TWO MOLECULES OF UMUD PRIME

287
00:13:14,534 --> 00:13:17,270
THE CLEAVED FORM OF UMUD AND

288
00:13:17,270 --> 00:13:21,908
MOLECULE OF UMUC. SUBSEQUENTLY

289
00:13:21,908 --> 00:13:24,710
ROGER AND GOODMAN'S LAB PURIFIED

290
00:13:24,710 --> 00:13:32,718
THIS PRIMER. THEN AFTER THIS

291
00:13:32,718 --> 00:13:34,087
RATHER MANY YEARS WHERE VERY

292
00:13:34,087 --> 00:13:35,988
LITTLE HAPPENED THERE WAS A

293
00:13:35,988 --> 00:13:38,991
MAJOR REVOLUTION IN 1999, THE

294
00:13:38,991 --> 00:13:43,196
YEAR OF THE NEW POLYMERASES.  SO

295
00:13:43,196 --> 00:13:44,864
LET'S GO THROUGH DRAMATIC EVENTS

296
00:13:44,864 --> 00:13:47,166
THAT HAPPENED IN THIS AREA JUST

297
00:13:47,166 --> 00:13:50,470
IN ONE YEAR. (INAUDIBLE) WAS

298
00:13:50,470 --> 00:13:52,805
IDENTIFIED AS A DNA POLYMER RACE

299
00:13:52,805 --> 00:13:57,310
POL 4 RELATED TO UMUC AND 30 BY

300
00:13:57,310 --> 00:14:01,314
GROUPS OF FOX AND M NOMI. IN

301
00:14:01,314 --> 00:14:02,982
1999, THREE GROUP -- TWO GROUPS

302
00:14:02,982 --> 00:14:07,186
FOUND UMUD PRIOR TO C WHAT IN

303
00:14:07,186 --> 00:14:08,955
FACT DNA POLYMERASE WE NOW KNOW

304
00:14:08,955 --> 00:14:13,826
AS POLV AND SHOWED POL 5 CAN

305
00:14:13,826 --> 00:14:15,428
CARRY OUT TRANSLESION SYNTHESIS.

306
00:14:15,428 --> 00:14:18,931
MOVING UP TO YEAST. ROGER'S

307
00:14:18,931 --> 00:14:20,600
GROUP AND CEDAR'S GROUP

308
00:14:20,600 --> 00:14:22,969
IDENTIFIED SEQUENCE IDENTITIES

309
00:14:22,969 --> 00:14:23,870
BETWEEN (INAUDIBLE) 30 IN YEAST

310
00:14:23,870 --> 00:14:25,304
AND THE E. COLI GENES THAT

311
00:14:25,304 --> 00:14:29,976
INDICATED HERE. IN 30 BEGINNING

312
00:14:29,976 --> 00:14:32,378
OF THE YEAR WAS FINALLY FOUND TO

313
00:14:32,378 --> 00:14:36,883
BE DNA POLYMERASE BY THE PRAKASH

314
00:14:36,883 --> 00:14:38,918
GROUP. ANOTHER DEVELOPMENT IN

315
00:14:38,918 --> 00:14:40,753
THE SAME YEAR, WAS THE

316
00:14:40,753 --> 00:14:42,288
DEVELOPMENT OF IN VITRO SYSTEMS

317
00:14:42,288 --> 00:14:46,325
WHICH WERE ABLE TO MIMIC THE

318
00:14:46,325 --> 00:14:48,661
DEFECTED XP VARIANTS. THE

319
00:14:48,661 --> 00:14:50,863
EXPERIMENT HERE IS TO TAKE --

320
00:14:50,863 --> 00:14:53,199
SELL EXTRACTS AND OFFER THEM

321
00:14:53,199 --> 00:14:57,069
PLASMID CONTAINING A SINGLE

322
00:14:57,069 --> 00:15:00,406
LESION. THEN LOOK AT THE ABILITY

323
00:15:00,406 --> 00:15:03,042
OF DIFFERENT EXTRACTS TO

324
00:15:03,042 --> 00:15:05,578
REPLICATE PAST DAMAGE IN THESE

325
00:15:05,578 --> 00:15:08,014
SUBSTRATES. HERE YOU CAN SEE ONE

326
00:15:08,014 --> 00:15:11,317
SUCH EXPERIMENT, THIS IS A

327
00:15:11,317 --> 00:15:13,953
RESULT OF (INAUDIBLE) LAB, SO IN

328
00:15:13,953 --> 00:15:18,491
NORMAL EXTRACTS, YOU CAN SEE

329
00:15:18,491 --> 00:15:19,091
HERE THE TRANSLATION SYNTHESIS

330
00:15:19,091 --> 00:15:22,628
GIVES THE BAND AT THIS POINT

331
00:15:22,628 --> 00:15:25,164
(INAUDIBLE). IF YOU LOOK AT XP

332
00:15:25,164 --> 00:15:28,034
VARIANT EXTRACTS HOWEVER, THEY

333
00:15:28,034 --> 00:15:30,469
STOPPED BLOCKED AT POSITION OF

334
00:15:30,469 --> 00:15:31,003
VERY LITTLE TRANSLATION

335
00:15:31,003 --> 00:15:33,639
SYNTHESIS.  THIS IS MORE -- SAME

336
00:15:33,639 --> 00:15:34,607
RESULT WITH SLIGHTLY DIFFERENT

337
00:15:34,607 --> 00:15:41,180
LESION.  SO USING ONE OF THESE

338
00:15:41,180 --> 00:15:41,981
SYSTEMS, (INAUDIBLE) GROUP

339
00:15:41,981 --> 00:15:44,283
PURIFIED THE PROTEIN THAT WAS

340
00:15:44,283 --> 00:15:47,453
DEFECTIVE IN XP -- THE EXTRACT

341
00:15:47,453 --> 00:15:48,721
SEQUENCE PEPTIDE SCREEN LIBRARY

342
00:15:48,721 --> 00:15:50,156
AND IDENTIFIED THE GENE AND

343
00:15:50,156 --> 00:15:53,459
FOUND MUTATIONS IN XPV PATIENTS

344
00:15:53,459 --> 00:15:55,595
FROM THIS PROTEIN WAS DNA

345
00:15:55,595 --> 00:15:59,899
POLYMERASE WHICH WE NOW KNOW IS

346
00:15:59,899 --> 00:16:02,868
(INAUDIBLE) HERE IS CRUCIAL

347
00:16:02,868 --> 00:16:04,070
EXPERIMENT, CRUCIAL RESULTS FROM

348
00:16:04,070 --> 00:16:07,139
THAT WORK SO THEY ARE USING AN

349
00:16:07,139 --> 00:16:08,040
OLIGONUCLEOTIDE SUB INVESTIGATE

350
00:16:08,040 --> 00:16:09,775
WITH A SINGLE PYRIMIDINE DIMER

351
00:16:09,775 --> 00:16:15,448
HERE.  WITHOUT DAMAGE BOTH

352
00:16:15,448 --> 00:16:18,551
PAULETTEA AND (INAUDIBLE)

353
00:16:18,551 --> 00:16:20,086
SYNTHESIZE RAD 30 NUCLEOTIDE,

354
00:16:20,086 --> 00:16:22,421
WHEREAS IF THERE IS A PYRIMIDINE

355
00:16:22,421 --> 00:16:25,758
DIMER HERE, YOU CAN SYNTHESIZE

356
00:16:25,758 --> 00:16:27,093
POL ALPHA IS BLOCKED AT THE

357
00:16:27,093 --> 00:16:29,395
LESION. THE MORE I

358
00:16:29,395 --> 00:16:33,633
SIMULTANEOUSLY PRAKASH GROUP RAD

359
00:16:33,633 --> 00:16:35,968
30 HOMOLOGUE AND FOUND HOMOLOGUE

360
00:16:35,968 --> 00:16:38,437
FROM THE GENE AND FOUND IN XPV

361
00:16:38,437 --> 00:16:44,043
PATIENTS AS WELL. SO CLEARLY

362
00:16:44,043 --> 00:16:45,544
PAULITA WAS A GENE PRODUCT

363
00:16:45,544 --> 00:16:49,181
LACKING IN XP VARIANTS. ROGER

364
00:16:49,181 --> 00:16:51,584
AND COLLEAGUES FOUND THE SECOND

365
00:16:51,584 --> 00:16:53,352
RAD 30 HOMOLOGUE, CALLED

366
00:16:53,352 --> 00:16:55,221
(INAUDIBLE) NOT FOUND TO BE

367
00:16:55,221 --> 00:16:58,724
MUTATED IN XP VARIANT PATIENT.

368
00:16:58,724 --> 00:17:01,494
LIKEWISE WAS A HOMOLOGUE WE KNOW

369
00:17:01,494 --> 00:17:05,564
AS POL KAPPA BUT HUMAN RED 1

370
00:17:05,564 --> 00:17:07,099
HOMOLOGUE ALSO BEEN IDENTIFIED.

371
00:17:07,099 --> 00:17:09,335
SO THIS RATHER STUNNING SERIES

372
00:17:09,335 --> 00:17:13,873
OF PAPERS ALL IN 1999, IF YOU

373
00:17:13,873 --> 00:17:18,144
LOOK BETWEEN JULY AND AUGUST --

374
00:17:18,144 --> 00:17:21,347
BETWEEN JUNE AND AUGUST, FIVE

375
00:17:21,347 --> 00:17:24,750
PAPERS XPV PROTEIN BEING

376
00:17:24,750 --> 00:17:26,185
HOMOLOGOUS TO RAD 30 BY THESE

377
00:17:26,185 --> 00:17:31,924
TWO GROUPS, UMUD THROUGH C POL 5

378
00:17:31,924 --> 00:17:35,194
PNAS AND HOMOLOGUE DNA

379
00:17:35,194 --> 00:17:38,831
POLYMERASE FORM. SO THE

380
00:17:38,831 --> 00:17:40,032
ASTONISHING YEAR WHICH REALLY

381
00:17:40,032 --> 00:17:43,502
COMPLETELY OVERTURNED THE

382
00:17:43,502 --> 00:17:46,038
TRANSLESION SYNTHESIS FIELD AND

383
00:17:46,038 --> 00:17:47,273
THAT IS WHERE I'M GOING TO LEAVE

384
00:17:47,273 --> 00:17:50,443
IT BECAUSE THE REST IS MODERN

385
00:17:50,443 --> 00:17:52,578
HISTORY AND I'M SURE MOST OF YOU

386
00:17:52,578 --> 00:17:54,480
KNOW THE DETAILS OR MANY OF THE

387
00:17:54,480 --> 00:17:59,218
DETAILS THAT HAVE BEEN GOING ON 

388
00:17:59,218 --> 00:18:01,120
SO NOW I'M GOING TO CHANGE TRACK

389
00:18:01,120 --> 00:18:03,756
COMPLETELY.  AND MOVER TO TELL

390
00:18:03,756 --> 00:18:05,991
YOU ABOUT THE MULTI-DISCIPLINARY

391
00:18:05,991 --> 00:18:06,859
CLINICS THAT WE HAVE ESTABLISHED

392
00:18:06,859 --> 00:18:10,496
IN THE UK.  THE FIRST IS THE UK

393
00:18:10,496 --> 00:18:13,599
MULTI-DISCIPLINARY CLINIC.  

394
00:18:13,599 --> 00:18:22,575
EXCUSE ME A MOMENT. ESTABLISHED

395
00:18:22,575 --> 00:18:25,111
BY MY DERMATOLOGY COLLEAGUE IN

396
00:18:25,111 --> 00:18:27,613
2010, WE NOW HAVE 120 XP

397
00:18:27,613 --> 00:18:29,281
PATIENTS PRETTY MUCH ALL THE XP

398
00:18:29,281 --> 00:18:32,585
PATIENTS IN THE UK VISITING ON A

399
00:18:32,585 --> 00:18:34,253
REGULAR BASIS.  TYPICALLY ONCE A

400
00:18:34,253 --> 00:18:35,888
YEAR BUT IN SOME CASES MORE

401
00:18:35,888 --> 00:18:42,094
OFTEN IF THEY NEED MOB

402
00:18:42,094 --> 00:18:52,705
WOKSMEMORE WOR WORK.CRUCIAL ROLN

403
00:18:52,705 --> 00:18:54,607
AT THE BOTTOM HERE I'M VERY MUCH

404
00:18:54,607 --> 00:18:59,912
PART TIME CONSULTANT SCIENTIST. 

405
00:18:59,912 --> 00:19:02,148
SO HERE IS A DISTRIBUTION OF

406
00:19:02,148 --> 00:19:03,883
DIFFERENT COMPLEMENTATION

407
00:19:03,883 --> 00:19:08,020
GROUPS. 22 XPA WHICH DIVIDED TO

408
00:19:08,020 --> 00:19:09,622
TWO GROUPS WILL BECOME CLEAR IN

409
00:19:09,622 --> 00:19:14,560
A MOMENT. JUST ONE XPV, NONE OF

410
00:19:14,560 --> 00:19:17,530
XPC, FAIR NUMBER OF DNA

411
00:19:17,530 --> 00:19:20,332
VARIANTS, EF AND G, SIMILAR TO

412
00:19:20,332 --> 00:19:22,535
WHAT OTHER GROUPS REPORTED IN

413
00:19:22,535 --> 00:19:25,771
OTHER -- IN DIFFERENT PARTS OF

414
00:19:25,771 --> 00:19:28,374
THE WORLD. OF THE WEST.

415
00:19:28,374 --> 00:19:29,809
COMPLETELY DIFFERENT IN JAPAN.

416
00:19:29,809 --> 00:19:34,246
LET'S LOOK AT THE XPA PATIENTS. 

417
00:19:34,246 --> 00:19:36,849
LOOK A AT LINE HERE YOU SEE 8 OR

418
00:19:36,849 --> 00:19:38,751
9 XPA PATIENTS WHICH ARE

419
00:19:38,751 --> 00:19:41,754
TEXTBOOK PATIENTS, VERY SEVERE

420
00:19:41,754 --> 00:19:44,857
THEY TYPICALLY GOT TRUNCATION

421
00:19:44,857 --> 00:19:47,326
MUTATION. NEUROLOGISTS DEVELOPED

422
00:19:47,326 --> 00:19:51,363
A NEUROSTORE WITH A MAXIMUM OF 8

423
00:19:51,363 --> 00:19:54,300
YOU CAN SEE THEY HAVE SEVERE

424
00:19:54,300 --> 00:19:56,735
NEUROLOGICAL ABNORMALITIES,

425
00:19:56,735 --> 00:19:59,171
THEIR AGE IS OVER HERE. SO THIS

426
00:19:59,171 --> 00:20:01,073
IS WHAT YOU CAN READ IN MANY

427
00:20:01,073 --> 00:20:02,741
EARLIER PAPERS.  CONTRAST THAT

428
00:20:02,741 --> 00:20:06,145
WITH THE ONES BELOW THE LINE.  

429
00:20:06,145 --> 00:20:08,147
NONE HAVE NEUROLOGICAL PROBLEMS.

430
00:20:08,147 --> 00:20:10,983
THEY ALL HAVE THE SAME MUTATION.

431
00:20:10,983 --> 00:20:17,490
OF THE 8 BASE INTRON 4 AND A TO

432
00:20:17,490 --> 00:20:24,230
JJ. HERE IS ONE OF THE FIRST ONS

433
00:20:24,230 --> 00:20:28,767
MISDEMEANOR WERE SUN SORNED WORK

434
00:20:28,767 --> 00:20:29,869
OUTDOORS AS A (INAUDIBLE) UNTIL

435
00:20:29,869 --> 00:20:32,471
HE MOVEDDED TO THE UK AT AGE 32.

436
00:20:32,471 --> 00:20:34,673
DIDN'T HAVE ANY SKIN CANCER

437
00:20:34,673 --> 00:20:37,610
UNTIL 65, NO NEUROLOGY AT ALL,

438
00:20:37,610 --> 00:20:39,845
HE DIED A COUPLE OF YEARS AGO IN

439
00:20:39,845 --> 00:20:44,250
HIS '80s.  HERE ARE THREE MORE

440
00:20:44,250 --> 00:20:47,219
WITH RELATIVELY MINOR SKIN

441
00:20:47,219 --> 00:20:49,288
PROBLEMS, NO SKIN CANCER, NO

442
00:20:49,288 --> 00:20:50,422
NEUROLOGY, EVEN THOUGH THEY

443
00:20:50,422 --> 00:20:51,790
DON'T PROTECT THEMSELVES PRETTY

444
00:20:51,790 --> 00:20:57,530
WELL. SO WHAT IS GOING ON HERE?

445
00:20:57,530 --> 00:20:58,631
ALL THESE INDIVIDUALS COME FROM

446
00:20:58,631 --> 00:21:00,933
THIS AREA OF NORTHERN INDIA,

447
00:21:00,933 --> 00:21:01,734
NORTHERN PAKISTAN AND

448
00:21:01,734 --> 00:21:06,105
AFGHANISTAN. SUGGESTING STRONGLY

449
00:21:06,105 --> 00:21:07,873
THERE IS A FOUNDER EFFECT AT

450
00:21:07,873 --> 00:21:10,576
THAT LOCATION.  SO WHAT IS GOING

451
00:21:10,576 --> 00:21:13,646
ON? THE SPLICE MUTATION

452
00:21:13,646 --> 00:21:15,881
INDICATES WHY THEIR UDS IS LOW. 

453
00:21:15,881 --> 00:21:19,752
AND THIS MUTATION GENERATES A

454
00:21:19,752 --> 00:21:21,520
NEW (INAUDIBLE) FROM THE 8TH

455
00:21:21,520 --> 00:21:23,656
BASE HERE WHICH RESULTS IN THE

456
00:21:23,656 --> 00:21:26,525
INSERTION OF SEVEN BASES BETWEEN

457
00:21:26,525 --> 00:21:28,761
EXON 4 AND 5 WHICH IS WHAT IS

458
00:21:28,761 --> 00:21:29,828
THE SEQUENCE -- PUTS THE

459
00:21:29,828 --> 00:21:31,063
SEQUENCE OUT OF FRAME AND

460
00:21:31,063 --> 00:21:34,099
RESULTS IN A SEVERERY TRUNCATED

461
00:21:34,099 --> 00:21:36,869
PROTEIN. SO WHY THE SYMPTOM IS

462
00:21:36,869 --> 00:21:39,405
SO MILD, WE FOUND IT WAS

463
00:21:39,405 --> 00:21:41,206
APPROXIMATELY 5% OF NORMAL

464
00:21:41,206 --> 00:21:45,144
MESSENGER RNA BEING MADE.  WHEN

465
00:21:45,144 --> 00:21:48,380
WE WENT TO FURTHER AND LOOK AT

466
00:21:48,380 --> 00:21:52,017
XPA PROTEIN, WE GOT RESULTS

467
00:21:52,017 --> 00:21:54,887
HERE. ON THE LEFT-HAND SIDE WE

468
00:21:54,887 --> 00:21:56,622
HAVE CALIBRATION OF INCREASING

469
00:21:56,622 --> 00:21:58,691
AMOUNTS OF NORMAL EXTRACT. ON

470
00:21:58,691 --> 00:22:02,895
THE RIGHT HAND SIDE WE HAVE 50

471
00:22:02,895 --> 00:22:04,363
MILLIGRAMS OF EXTRACT FROM

472
00:22:04,363 --> 00:22:06,699
NORMAL INDIVIDUALS BOTH FROM XPA

473
00:22:06,699 --> 00:22:08,100
PROTEIN. ON THE RIGHT HAND SIDE

474
00:22:08,100 --> 00:22:11,437
WE HAVE XPA NULL WITH NO BANDS

475
00:22:11,437 --> 00:22:12,972
IN THIS POSITION BUT FOUR OF

476
00:22:12,972 --> 00:22:16,375
THESE WITH THE INTRON MUTATION

477
00:22:16,375 --> 00:22:19,678
YOU CAN SEE SMALL AMOUNTS OF XPA

478
00:22:19,678 --> 00:22:22,214
PROTEIN MADE CORRESPONDING TO 5%

479
00:22:22,214 --> 00:22:28,988
OF XPA PROTEIN. IF WE LOOK MORE

480
00:22:28,988 --> 00:22:30,789
CAREFULLY AT SCHEDULE DNA

481
00:22:30,789 --> 00:22:34,727
SYNTHESIS, NORMAL RESPONSE XPA

482
00:22:34,727 --> 00:22:36,528
NULL YOU CAN SEE A SMALL AMOUNT

483
00:22:36,528 --> 00:22:39,431
OF UNSCHEDULED DNA SYNTHESIS IN

484
00:22:39,431 --> 00:22:42,301
THESE INDIVIDUALS WITH XPA

485
00:22:42,301 --> 00:22:47,172
INTRONNIC MUTATION.  SO IT SEEMS

486
00:22:47,172 --> 00:22:49,041
THAT IN XPA THE VERY LOW LEVEL

487
00:22:49,041 --> 00:22:51,477
OF RESIDUAL REPAIR IS SUFFICIENT

488
00:22:51,477 --> 00:22:54,647
TO ALLEVIATE NEUROLOGICAL

489
00:22:54,647 --> 00:22:55,914
PROBLEMS AND MANY OTHER SKIN

490
00:22:55,914 --> 00:22:59,351
PROBLEMS AS WELL. SO WE HAVE

491
00:22:59,351 --> 00:23:02,221
DEFINITIVE EVIDENCE HERE THE

492
00:23:02,221 --> 00:23:04,023
LIFE MUTATION LEAVING IN SMALL

493
00:23:04,023 --> 00:23:05,324
AMOUNT OF NORMAL SPLICING CAN

494
00:23:05,324 --> 00:23:10,129
GIVE RELATIVELY MILD SYMPTOMS.

495
00:23:10,129 --> 00:23:12,331
AND KRAMER ALSO REPORTED SIMILAR

496
00:23:12,331 --> 00:23:14,333
THINGS WITH AN XPC PATIENT. WE

497
00:23:14,333 --> 00:23:15,601
HAVE SEVERAL OTHER PATIENTS WE

498
00:23:15,601 --> 00:23:17,269
THINK WE MIGHT SEE THE SAME --

499
00:23:17,269 --> 00:23:19,171
BE SEEING THE SAME THING IN

500
00:23:19,171 --> 00:23:21,206
DIFFERENT XP GROUPS BUT WE DON'T

501
00:23:21,206 --> 00:23:23,208
HAVE COMPLETE DEFINITIVE

502
00:23:23,208 --> 00:23:27,212
EVIDENCE INDICATED HERE. NOW

503
00:23:27,212 --> 00:23:31,950
MOVING TO XPD. HERE IS THE TWO

504
00:23:31,950 --> 00:23:35,521
INDIVIDUALS SIMILAR AGE, AGE 25,

505
00:23:35,521 --> 00:23:39,024
IN THIS CASE 19, BOTH HAD SEVERE

506
00:23:39,024 --> 00:23:39,925
SUNBURNS FROM BIRTH BUT THEY

507
00:23:39,925 --> 00:23:41,593
HAVE BEEN REALLY FANTASTICICALLY

508
00:23:41,593 --> 00:23:43,162
WELL PROTECT SOD THEY HAVE NO

509
00:23:43,162 --> 00:23:47,633
SKIN LESIONS AT ALL. THE ONE ON

510
00:23:47,633 --> 00:23:50,402
THE LEFT HAD RECURSIVE

511
00:23:50,402 --> 00:23:51,770
NEUROLOGICAL DISEASE FROM AGE 7

512
00:23:51,770 --> 00:23:54,173
YOU CAN SEE THE SYMPTOMS HERE.

513
00:23:54,173 --> 00:23:57,643
HE SADLY DIED A FEW YEARS AGO

514
00:23:57,643 --> 00:23:58,744
AGE 28. THIS YOUNG MAN NOW ABOUT

515
00:23:58,744 --> 00:24:01,013
THE SAME AGE, 28 HAS HAD NO

516
00:24:01,013 --> 00:24:03,315
NEUROLOGICAL PROBLEMS AT ALL. IF

517
00:24:03,315 --> 00:24:05,651
WE LOOK AT MUTATIONS, THEY

518
00:24:05,651 --> 00:24:09,521
MUTATED AT THE SAME AMINO ACID

519
00:24:09,521 --> 00:24:12,324
ARGININE 683. IN THIS CASE A

520
00:24:12,324 --> 00:24:13,025
TRYPTOPHAN BUT IN THIS CASE

521
00:24:13,025 --> 00:24:18,230
GLUTAMINE.  HERE IS ONE OF THE

522
00:24:18,230 --> 00:24:20,099
3-D STRUCTURE OF THE XPD

523
00:24:20,099 --> 00:24:23,035
PROTEIN. THIS ONE GENERATED BY

524
00:24:23,035 --> 00:24:25,537
THE (INAUDIBLE) GROUP, ARGININE

525
00:24:25,537 --> 00:24:28,841
683 DOWN HERE. BUT IF WE FOCUS

526
00:24:28,841 --> 00:24:32,811
IN ON ARGININE 683 WE SEE HERE

527
00:24:32,811 --> 00:24:36,915
IT HAS INTERACTIONS WITH

528
00:24:36,915 --> 00:24:39,485
ASPARTATE 681 WHERE THE DNA IS

529
00:24:39,485 --> 00:24:43,889
INDICATED BY THIS PURPLE LINE. 

530
00:24:43,889 --> 00:24:47,793
SO HERE IS ARGININE AS A

531
00:24:47,793 --> 00:24:48,927
BIOCHEMIST AMONG YOU OBVIOUSLY

532
00:24:48,927 --> 00:24:50,996
KNOW.  THIS IS GLUTAMINE WHICH

533
00:24:50,996 --> 00:24:53,932
YOU CAN SEE IT IS SMALLER, IT IS

534
00:24:53,932 --> 00:24:55,634
NEUTRAL AS OPPOSED TO ARGININE

535
00:24:55,634 --> 00:24:56,969
WHICH IS POSITIVELY CHARGED BUT

536
00:24:56,969 --> 00:24:59,171
IT IS HYDROPHILIC AND PROBABLY

537
00:24:59,171 --> 00:25:02,040
SIT IN HERE QUITE COMFORTABLY

538
00:25:02,040 --> 00:25:03,242
WITH SOMEWHAT WEAKER

539
00:25:03,242 --> 00:25:05,244
INTERACTIONS.  THIS IS THE

540
00:25:05,244 --> 00:25:08,347
MUTATION, MUTATED AMINO ACID IN

541
00:25:08,347 --> 00:25:09,815
THE YOUNG MAN ON THE RIGHT WITH

542
00:25:09,815 --> 00:25:14,253
NO NEUROLOGICAL PROBLEMS. WHERE

543
00:25:14,253 --> 00:25:16,121
TRYPTOPHAN AROMATIC SIDE CHAIN

544
00:25:16,121 --> 00:25:19,358
IS LIKELY TO BLOW THIS AREA

545
00:25:19,358 --> 00:25:20,926
APART AND PROBABLY ACCOUNTS FOR

546
00:25:20,926 --> 00:25:23,195
WHY MORE SEVERELY AFFECTED YOUNG

547
00:25:23,195 --> 00:25:25,197
MAN HAD THOSE SEVERE

548
00:25:25,197 --> 00:25:29,802
NEUROLOGICAL PROBLEMS. NOW, A

549
00:25:29,802 --> 00:25:34,840
FEW WORDS ABOUT XPF. WE HAVE

550
00:25:34,840 --> 00:25:37,509
SEVERAL XPF PATIENTS, THEY ARE

551
00:25:37,509 --> 00:25:39,812
ALL NOT THAT YOUNG BUT NONE HAD

552
00:25:39,812 --> 00:25:40,846
ANY SKIN CANCERS EVEN THOUGH

553
00:25:40,846 --> 00:25:42,748
THEY HAVEN'T NECESSARILY BEEN

554
00:25:42,748 --> 00:25:47,820
THAT WELL PROTECTED.  HERE ARE

555
00:25:47,820 --> 00:25:51,056
TWO OF THEM, YOUNG MEN. NOW A

556
00:25:51,056 --> 00:25:57,329
FEW YEARS OLDER. THEY BURN

557
00:25:57,329 --> 00:25:59,431
EASILY, TAKING TWO WEEKS TO

558
00:25:59,431 --> 00:26:00,999
RESOLVE REASONABLE BUT NOT

559
00:26:00,999 --> 00:26:02,668
RIGOROUS PROTECTION BUT THEY

560
00:26:02,668 --> 00:26:04,670
HAVE VERY FEW SKIN CHANGES, SOME

561
00:26:04,670 --> 00:26:06,438
YOU WOULDN'T THINK HAD XP AT

562
00:26:06,438 --> 00:26:07,873
ALL. NO NEUROLOGICAL PROBLEMS AT

563
00:26:07,873 --> 00:26:18,317
ALL.  THIS LADY, EXAGGERATED

564
00:26:18,317 --> 00:26:20,419
SUNBURN, YET SOME SUN PROTECTION

565
00:26:20,419 --> 00:26:22,554
BUT SHE WASN'T DIAGNOSED UNTIL

566
00:26:22,554 --> 00:26:24,423
SHE WAS 29. SHE HAD NO SKIN

567
00:26:24,423 --> 00:26:26,291
CANCER U YOU CAN SEE HER SKIN

568
00:26:26,291 --> 00:26:31,063
FEATURES ARE RELATIVELY MIL MILN

569
00:26:31,063 --> 00:26:32,965
HER LATER LIFE SHE DEVELOPED

570
00:26:32,965 --> 00:26:34,066
PROGRESSIVE NEUROLOGICAL

571
00:26:34,066 --> 00:26:36,735
PROBLEMS AS YOU CAN SEE HERE,

572
00:26:36,735 --> 00:26:38,871
DEAFNESS, DISABILITY, ATAXIA,

573
00:26:38,871 --> 00:26:41,306
AND SHE SADLY DIED COUPLE OF

574
00:26:41,306 --> 00:26:42,307
YEARS AGO FROM AN INTERNAL

575
00:26:42,307 --> 00:26:47,713
TUMOR. SO THESE TWO YOUNG MEN I

576
00:26:47,713 --> 00:26:52,651
SHOWED YOU A MINUTE AGO, MUTATED

577
00:26:52,651 --> 00:26:59,057
AT PROLINE 379 TO SERINE. SO NO

578
00:26:59,057 --> 00:27:02,928
NEURO ASSOCIATED WITH THOSE.

579
00:27:02,928 --> 00:27:06,198
ARGININE 589 TO TRYPTOPHAN, THE

580
00:27:06,198 --> 00:27:08,367
NO KNOWN MUTATION. THE ARGININE

581
00:27:08,367 --> 00:27:10,035
799 THERE'S SEVERAL PATIENTS

582
00:27:10,035 --> 00:27:11,603
REPORTED SEEM TO BE ASSOCIATED

583
00:27:11,603 --> 00:27:15,474
WITH LATE ONSET NEUROLOGY. SO

584
00:27:15,474 --> 00:27:17,509
YOU CAN ASSOCIATE DIFFERENT

585
00:27:17,509 --> 00:27:18,243
MUTATIONS WITH DIFFERENT

586
00:27:18,243 --> 00:27:19,511
CLINICAL PHENOTYPES. T I WANT TO

587
00:27:19,511 --> 00:27:20,379
SAY A LITTLE BIT MORE ABOUT THIS

588
00:27:20,379 --> 00:27:26,585
ONE.  WE FOUND THIS MUTATION IN

589
00:27:26,585 --> 00:27:32,090
THREE MILD XPF PATIENTS. AND

590
00:27:32,090 --> 00:27:36,161
THIS ALTERATION IS THE IN THE

591
00:27:36,161 --> 00:27:38,497
HUMAN SLIP DATABASE, YOU CAN SEE

592
00:27:38,497 --> 00:27:40,465
OF NULL .3%. THE EVIDENCE OF

593
00:27:40,465 --> 00:27:42,901
THAT IS FREQUENCY OF HOMOZYGOTES

594
00:27:42,901 --> 00:27:44,102
IN THIS MUTATION IN THE

595
00:27:44,102 --> 00:27:46,104
POPULATION IS 10 TO THE MINUS 5

596
00:27:46,104 --> 00:27:48,140
SO THIS IS ABOUT FIVE TIMES

597
00:27:48,140 --> 00:27:51,743
HIGHER THAN THE PRE-CONCEIVED HP

598
00:27:51,743 --> 00:27:54,079
WESTERN EUROPE AND USA SO IN THE

599
00:27:54,079 --> 00:27:56,848
UK PROBABLY ABOUT 500 TO 1,000

600
00:27:56,848 --> 00:27:58,784
PEOPLE WITH THIS MUTATION

601
00:27:58,784 --> 00:28:00,118
HOMOZYGOUS FOR THIS MUTATION.

602
00:28:00,118 --> 00:28:01,586
AND WE JUST DON'T KNOW IF THEY

603
00:28:01,586 --> 00:28:04,790
ARE JUST GOING TO BE SUN

604
00:28:04,790 --> 00:28:06,458
SENSITIVE OR DEVELOP OTHER XP

605
00:28:06,458 --> 00:28:09,761
SYMPTOMS LATER ON IN LIFE. I

606
00:28:09,761 --> 00:28:11,763
SHOULD SAY THAT BEN KRAMERS

607
00:28:11,763 --> 00:28:12,965
GROUP REPORTED DID A SIMILAR

608
00:28:12,965 --> 00:28:15,667
ANALYSIS USING BIG DATA AND GOT

609
00:28:15,667 --> 00:28:16,802
VERY SIMILAR RESULTS.MENT I

610
00:28:16,802 --> 00:28:18,904
THINK CALCULATED SHOULD BE

611
00:28:18,904 --> 00:28:20,138
SEVERAL THOUSAND INDIVIDUALS

612
00:28:20,138 --> 00:28:22,274
HOMOZYGOUS FOR THIS MUTATION.  

613
00:28:22,274 --> 00:28:28,613
IN THE USA. NOW WE WILL FOCUS ON

614
00:28:28,613 --> 00:28:31,483
TWO XP PATIENTS WHO HAVE GOT

615
00:28:31,483 --> 00:28:33,118
SOME -- WITH RATHER REMARKABLE

616
00:28:33,118 --> 00:28:36,421
FINDINGS.  SO THIS IS A YOUNG

617
00:28:36,421 --> 00:28:39,658
MAN WITH XPC, AND HE HAD THIS

618
00:28:39,658 --> 00:28:42,461
VERY UNPLEASANT ANGIOSARCOMA

619
00:28:42,461 --> 00:28:44,229
JUST ABOVE HIS EYE. IT WAS

620
00:28:44,229 --> 00:28:47,399
EXTREMELY MALIGNANT AND RESULTED

621
00:28:47,399 --> 00:28:48,834
IN NAY STASIS IN SEVERAL ORGANS

622
00:28:48,834 --> 00:28:51,436
AND HERE YOU CAN SEE THIS BIG

623
00:28:51,436 --> 00:28:53,138
CANCER ON THE SIDE OF HIS MOUTH

624
00:28:53,138 --> 00:28:56,875
AND ACTUALLY HAD RECESSIVE IN --

625
00:28:56,875 --> 00:28:58,643
METASTASIS IN MANY ORGANS. HE

626
00:28:58,643 --> 00:28:59,611
WAS CLOSE WITHIN THREE WEEKS OF

627
00:28:59,611 --> 00:29:06,318
DEATH. SO FROM ACADEMICALLY,

628
00:29:06,318 --> 00:29:08,420
WHAT WOULD BE FOUND IN HIS

629
00:29:08,420 --> 00:29:11,390
TUMOR. WE WERE COLLABORATING

630
00:29:11,390 --> 00:29:12,958
WITH (INAUDIBLE) IN CAMBRIDGE

631
00:29:12,958 --> 00:29:14,426
AND ASKED IF SHE WOULD BE

632
00:29:14,426 --> 00:29:17,295
INTERESTED IN SEQUENCING THESE

633
00:29:17,295 --> 00:29:19,598
TUMORS DNA WHICH SHE DID. AND

634
00:29:19,598 --> 00:29:24,703
FOUND SOME REMARKABLE RESULTS.

635
00:29:24,703 --> 00:29:26,705
THE OTHER THING SHE FOUND IS

636
00:29:26,705 --> 00:29:28,140
EXTREMELY HIGH LEVEL OF

637
00:29:28,140 --> 00:29:32,077
MUTATION. IF YOU TAKE IT WITH

638
00:29:32,077 --> 00:29:33,545
MANY FOLD HIGHER THAN THE

639
00:29:33,545 --> 00:29:37,682
HIGHEST BREAST CANCER TUMOR DNA

640
00:29:37,682 --> 00:29:38,750
SHE HAD BEEN -- ANALYZED THE

641
00:29:38,750 --> 00:29:39,951
WHOLE SEQUENCE AND SO THE

642
00:29:39,951 --> 00:29:41,887
MUTATION FREQUENCY EXTREMELY

643
00:29:41,887 --> 00:29:43,555
HIGH. AND WHAT HER SPECIALTY IS

644
00:29:43,555 --> 00:29:46,558
IS LOOKING AT MUTATION

645
00:29:46,558 --> 00:29:50,328
SIGNATURES. LOOK AT THE TYPES OF

646
00:29:50,328 --> 00:29:51,663
MUTATIONS IN CANCER GENOMES

647
00:29:51,663 --> 00:29:54,266
COMPARED WITH THE GENOMES --

648
00:29:54,266 --> 00:29:55,767
COMPARED WITH THE GENOME WITH

649
00:29:55,767 --> 00:29:58,236
THE SAME INDIVIDUAL IN THEIR

650
00:29:58,236 --> 00:29:59,671
BLOOD. SO FINDINGS SHE MADE

651
00:29:59,671 --> 00:30:03,809
FIRST OF ALL NOT VERY

652
00:30:03,809 --> 00:30:05,177
SURPRISINGLY 91% HAD SIGNATURE 7

653
00:30:05,177 --> 00:30:07,913
WHICH IS A SIGNATURE EXPECTED

654
00:30:07,913 --> 00:30:11,016
FOR UV INDUCED MUTATION.  MUCH

655
00:30:11,016 --> 00:30:14,853
MORE INTERESTINGLY, SHE FOUND

656
00:30:14,853 --> 00:30:18,757
THAT 9% HAD SIGNATURE 10.

657
00:30:18,757 --> 00:30:20,959
SIGNATURE 10 IS ASSOCIATED WITH

658
00:30:20,959 --> 00:30:24,062
DRIVER MUTATIONS IN THE

659
00:30:24,062 --> 00:30:25,797
EXONUCLEASE DOMAIN POL EPSILON

660
00:30:25,797 --> 00:30:27,766
AND FURTHER ANALYSIS THEY FOUND

661
00:30:27,766 --> 00:30:31,403
INDEED A SERIES OF FEENAL

662
00:30:31,403 --> 00:30:34,539
ALANINE CHAIN AT AMINO ACID 459

663
00:30:34,539 --> 00:30:38,844
IN 17% OF THE TUMOR POPULATION. 

664
00:30:38,844 --> 00:30:40,378
SHE TOLD US HIGH MUTATIONAL

665
00:30:40,378 --> 00:30:43,248
BURDEN AND SOMATIC MUTATIONS IN

666
00:30:43,248 --> 00:30:46,585
POL EPSILON WERE YOU ARE THE

667
00:30:46,585 --> 00:30:48,120
REPORTED PREDICTIVE OF

668
00:30:48,120 --> 00:30:49,654
SENSITIVITY FOR IMMUNE CHECK

669
00:30:49,654 --> 00:30:51,289
POINT INHIBITORS.  NOW THERE WAS

670
00:30:51,289 --> 00:30:52,657
A PROBLEM BECAUSE IMMUNE CHECK

671
00:30:52,657 --> 00:30:54,226
POINT INHIBITORS ARE NOT

672
00:30:54,226 --> 00:30:56,661
LICENSED OR NOT USED GENERALLY

673
00:30:56,661 --> 00:30:59,431
FOR ANGIOSARCOMAS BECAUSE THEY

674
00:30:59,431 --> 00:31:01,633
HAVEN'T BEEN EFFECTIVE. AFTER A

675
00:31:01,633 --> 00:31:04,636
LOT OF DISCUSSION WITH

676
00:31:04,636 --> 00:31:06,104
DERMATOLOGIST PERSUADED THE

677
00:31:06,104 --> 00:31:08,073
ONCOLOGIST TO BE TREATED LIKE A

678
00:31:08,073 --> 00:31:09,141
MELANOMA AND SHOULD BE TREATED

679
00:31:09,141 --> 00:31:10,175
WITH THESE CHECK POINT

680
00:31:10,175 --> 00:31:12,711
INHIBITORS. THE RESULTS BEFORE

681
00:31:12,711 --> 00:31:16,248
DRAMATIC. AFTER A FEW WEEKS

682
00:31:16,248 --> 00:31:18,583
TREATMENT YOU CAN SEE THIS BIG

683
00:31:18,583 --> 00:31:20,485
TUMORS COMPLETELY GONE,

684
00:31:20,485 --> 00:31:22,420
METASTASIS IN THE LIVER HAVE

685
00:31:22,420 --> 00:31:24,789
COMPLETELY GONE. AND FIVE YEARS

686
00:31:24,789 --> 00:31:28,226
ON THIS GUY IS DOING VERY WELL,

687
00:31:28,226 --> 00:31:29,794
SERENA GAVE A TALK AT THE ROYAL

688
00:31:29,794 --> 00:31:31,263
SOCIETY EARLIER THIS YEAR AND

689
00:31:31,263 --> 00:31:33,498
THIS YOUNG MAN WAS SITTING NEXT

690
00:31:33,498 --> 00:31:36,201
TO ME, SERENA TALKED ABOUT HIM

691
00:31:36,201 --> 00:31:37,736
AMONG OTHER THINGS AND HE WAS TO

692
00:31:37,736 --> 00:31:39,271
SOME EXTENT THE STAR OF THE SHOW

693
00:31:39,271 --> 00:31:44,376
THERE. DRAMATIC ILLUSTRATION HOW

694
00:31:44,376 --> 00:31:46,611
MOLECULAR ANALYSIS OF A TUMOR

695
00:31:46,611 --> 00:31:52,417
CAN DIRECT THERAPY. SO NOW

696
00:31:52,417 --> 00:31:54,319
JUMPING TO THE SECOND PATIENT,

697
00:31:54,319 --> 00:31:57,956
MUCH MORE RECENTLY JUST A FEW

698
00:31:57,956 --> 00:32:01,726
MONTHS AGO THE CLINIC, A

699
00:32:01,726 --> 00:32:04,362
6-YEAR-OLD CHILD BROUGHT, FIRST

700
00:32:04,362 --> 00:32:05,497
CHILD WITH UNRELATED HEALTH

701
00:32:05,497 --> 00:32:07,132
PARENTS AND SHE HAD ALL THE

702
00:32:07,132 --> 00:32:11,102
CLINICAL FEATURES OF XP, EXTREME

703
00:32:11,102 --> 00:32:14,706
SUNBURN, PROGRESSIVE FACIAL,

704
00:32:14,706 --> 00:32:16,575
FRECKLES IN THE FACE. SO WE

705
00:32:16,575 --> 00:32:19,277
LOOKED AT SCHEDULE DNA

706
00:32:19,277 --> 00:32:20,712
SYNTHESIS, CLEARLY CONSISTENT

707
00:32:20,712 --> 00:32:23,448
WITH DIAGNOSIS WITH XP VERY MUCH

708
00:32:23,448 --> 00:32:25,650
REDUCED. WHEN THE MOLECULAR

709
00:32:25,650 --> 00:32:27,719
ANALYSIS WAS DONE BY OUR

710
00:32:27,719 --> 00:32:28,453
COLLEAGUES IN (INAUDIBLE)

711
00:32:28,453 --> 00:32:31,690
HOSPITAL USING A PLATFORM OF 14

712
00:32:31,690 --> 00:32:34,392
GENES KNOWN TO BE DEFECTIVE IN

713
00:32:34,392 --> 00:32:37,262
XP OR GGD, NO MUTATION WAS FOUND

714
00:32:37,262 --> 00:32:40,799
IN ANY OF THE 14 NER GENES.  SO

715
00:32:40,799 --> 00:32:45,537
WE THEN CALLED ON MORE OF OUR

716
00:32:45,537 --> 00:32:46,805
FRIENDS FROM A (INDISCERNIBLE)

717
00:32:46,805 --> 00:32:48,573
IN JAPAN AND ASKED WOULD THEY BE

718
00:32:48,573 --> 00:32:50,675
ABLE TO DO WHOLE GENOME

719
00:32:50,675 --> 00:32:53,078
SEQUENCING OR EOME SEQUENCING TO

720
00:32:53,078 --> 00:32:58,283
TRY AND FIND THE DEFECTIVE GENE.

721
00:32:58,283 --> 00:32:59,884
THE ONLY THREE WHICH THEY CAME

722
00:32:59,884 --> 00:33:02,954
UP WITH THE GOODS. SO THEY ALOUD

723
00:33:02,954 --> 00:33:04,656
ME TO PRESENT SOME OF THEIR DATA

724
00:33:04,656 --> 00:33:06,491
WHICH IS NOT YET PUBLISHED. SO

725
00:33:06,491 --> 00:33:10,262
FIRST OF ALL THEY CONFIRMED OUR

726
00:33:10,262 --> 00:33:11,963
FINDINGS WITH NO DEFECT IN ANY

727
00:33:11,963 --> 00:33:15,567
OF THE KNOWN GENES SO THIS IS BY

728
00:33:15,567 --> 00:33:17,602
LENTIVIRUS INFECTION WITH THESE

729
00:33:17,602 --> 00:33:20,338
DIFFERENT CDNAs AND NONE OF

730
00:33:20,338 --> 00:33:22,240
THE CORRECTED ON SCHEDULE DNA

731
00:33:22,240 --> 00:33:24,476
SYNTHESIS THAT YOU CAN SEE HERE

732
00:33:24,476 --> 00:33:29,047
IN ALL INDIVIDUALS.  WHOLE

733
00:33:29,047 --> 00:33:31,149
GENOME SEQUENCING IDENTIFIED

734
00:33:31,149 --> 00:33:35,353
PATHOGENIC MUTATIONS IN THE GENE

735
00:33:35,353 --> 00:33:38,623
GTF 2H 4 WHICH ENCODES THE P 52

736
00:33:38,623 --> 00:33:42,394
SUB UNIT OF TF 28. YOU KNOW TF

737
00:33:42,394 --> 00:33:46,298
28 CONTAINS HPD. THE XPD

738
00:33:46,298 --> 00:33:47,932
PROTEIN. SO HERE WE HAVE A

739
00:33:47,932 --> 00:33:50,302
MUTATION IN ANOTHER PROTEIN

740
00:33:50,302 --> 00:33:53,938
COMPONENT OF TF 2H. MUTATIONS

741
00:33:53,938 --> 00:33:57,042
THEY FOUND ONE IN THE SPLICED

742
00:33:57,042 --> 00:33:59,944
RECEPTOR SIDE OF INTRON 2. WHICH

743
00:33:59,944 --> 00:34:02,847
IS ALSO AN INFRAME COMPLETION

744
00:34:02,847 --> 00:34:04,716
DELETION OF EXON 3 DEGRADED. 

745
00:34:04,716 --> 00:34:07,585
THE OTHER ONE A DELETION

746
00:34:07,585 --> 00:34:09,654
INSERTION IN EXON 30 RESULTING

747
00:34:09,654 --> 00:34:11,222
IN A TRUNCATED PROTEIN. WHICH

748
00:34:11,222 --> 00:34:13,458
THEY FOUND WAS STABLE BUT

749
00:34:13,458 --> 00:34:16,661
MISSING THE C TERMINAL 6D AMINO

750
00:34:16,661 --> 00:34:18,963
ACIDS. SO HERE IS WESTERN BLOT

751
00:34:18,963 --> 00:34:23,601
USING ANTIBODY TO P 52. HERE IS

752
00:34:23,601 --> 00:34:25,170
THE FOUND IN NORMAL INDIVIDUALS

753
00:34:25,170 --> 00:34:29,708
AND HERE THEY ARE FOUND IN XP 4

754
00:34:29,708 --> 00:34:32,944
TFR IN THE PATIENT. THE FINAL

755
00:34:32,944 --> 00:34:34,112
CONFIRMATION THIS WAS THE CAUSE

756
00:34:34,112 --> 00:34:37,315
OF THE UV SENSITIVITY, THEY PUT

757
00:34:37,315 --> 00:34:43,154
THE GTF 2 H POL GENE BACK WHERE

758
00:34:43,154 --> 00:34:45,423
XP GENES NONE WERE ABLE TO

759
00:34:45,423 --> 00:34:47,592
COMPLIMENT THE UNSETTLED DNA

760
00:34:47,592 --> 00:34:49,494
SYNTHESSYNTHESIS. YOU CAN SEE HS

761
00:34:49,494 --> 00:34:52,097
GENE COMPLIMENTED IT PROVING IT

762
00:34:52,097 --> 00:34:54,265
WAS THE CAUSE OF THE DEFECTIVE

763
00:34:54,265 --> 00:35:03,808
UV RESPONSE. SO SUMMARY SLIDES

764
00:35:03,808 --> 00:35:07,579
TO THIS POINT. COMPLEMENTATION

765
00:35:07,579 --> 00:35:10,014
GROUPS XPA TO G WERE IDENTIFIED

766
00:35:10,014 --> 00:35:13,651
IN THE 1970s. SO NOW AFTER 44

767
00:35:13,651 --> 00:35:15,487
YEARS WE HAVE A NEW

768
00:35:15,487 --> 00:35:17,756
COMPLEMENTATION GROUP. WHAT MANY

769
00:35:17,756 --> 00:35:19,290
OF YOU PROBABLY DON'T KNOW IS

770
00:35:19,290 --> 00:35:21,059
THAT PATIENTS WERE ASSIGNED TO

771
00:35:21,059 --> 00:35:23,495
GROUPS H AND I IN THE 1980s

772
00:35:23,495 --> 00:35:25,997
BUT THAT WAS SUBSEQUENTLY FOUND

773
00:35:25,997 --> 00:35:29,167
TO BE ERRONEOUS AND THEY WERE

774
00:35:29,167 --> 00:35:32,670
RETRACTED. HOWEVER, IN ORDER TO

775
00:35:32,670 --> 00:35:34,572
AVOID POSSIBLE CONFUSION WHICH

776
00:35:34,572 --> 00:35:36,808
SUGGEST THE NEW COMPLEMENTATION

777
00:35:36,808 --> 00:35:40,378
GROUP XPJ. THESE PATHOGENIC

778
00:35:40,378 --> 00:35:41,913
MUTATIONS CAUSE A C TERMINAL

779
00:35:41,913 --> 00:35:44,783
TRUNCATION OF THE P 52 SUB UNIT

780
00:35:44,783 --> 00:35:47,852
AND AFFECT INTERACTIONS BETWEEN

781
00:35:47,852 --> 00:35:51,389
P 52 AND TF 2H. SUBUNITS DAMAGE

782
00:35:51,389 --> 00:35:53,591
AND EXCLUSIVELY AFFECT THE NER

783
00:35:53,591 --> 00:35:55,293
ACTIVITY THAT DON'T AFFECT TRAN

784
00:35:55,293 --> 00:35:56,961
-- THE OVERALL TRANSCRIPTIONAL

785
00:35:56,961 --> 00:36:01,933
ACTIVITY, THIS IS ALSO WORK OF

786
00:36:01,933 --> 00:36:04,302
TOMO AND YUKO WHICH I HAVEN'T

787
00:36:04,302 --> 00:36:07,105
SHOWN YOU. SO SUMMARIZING THE XP

788
00:36:07,105 --> 00:36:09,107
CLINIC WE FOUND A HUGE VARIATION

789
00:36:09,107 --> 00:36:11,609
IN PHENOTYPE BETWEEN AND WITHIN

790
00:36:11,609 --> 00:36:14,646
XP GROUP, COMPLEMENTATION GROUP

791
00:36:14,646 --> 00:36:15,980
MOLECULAR ANALYSIS IS IMPORTANT

792
00:36:15,980 --> 00:36:17,348
FOR PROGNOSIS AND I HAVE SHOWN

793
00:36:17,348 --> 00:36:20,351
THE EXAMPLE OF THE XPA SPLICE

794
00:36:20,351 --> 00:36:23,688
MUTATIONS AND THE XPD ARGININE

795
00:36:23,688 --> 00:36:26,991
683 TRYPTOPHAN COMPARED TO

796
00:36:26,991 --> 00:36:31,162
GLUTAMINE. I SHOWED YOU THAT XPA

797
00:36:31,162 --> 00:36:33,298
SPLICE MUTATION IN RESIDUAL

798
00:36:33,298 --> 00:36:34,532
ACTIVITY CAN AFFECT THE

799
00:36:34,532 --> 00:36:36,734
PHENOTYPE DRAMATICALLY, THAT IS

800
00:36:36,734 --> 00:36:38,069
PROBABLY ALSO TRUE WITH OTHER

801
00:36:38,069 --> 00:36:40,205
GROUPS BUT WE NEED TO UPDATE AND

802
00:36:40,205 --> 00:36:47,145
APPROVE THAT DEFINITIVELY. XPF I

803
00:36:47,145 --> 00:36:50,315
SHOWED WITH XPV I HAVEN'T TALKED

804
00:36:50,315 --> 00:36:52,317
ABOUT HAVE LOWER CANCER

805
00:36:52,317 --> 00:36:53,451
PRE-DISPOSITION. WHY WE DON'T

806
00:36:53,451 --> 00:36:54,819
KNOW AND THE QUESTION SHOULD IT

807
00:36:54,819 --> 00:36:55,353
AFFECT MANAGEMENT OF THE

808
00:36:55,353 --> 00:36:59,224
PATIENTS.  I SHOWED YOU CASE

809
00:36:59,224 --> 00:37:01,793
WHERE MUTATION ANALYSIS NAY MAY

810
00:37:01,793 --> 00:37:04,429
DIRECT THERAPY AND THE NEW

811
00:37:04,429 --> 00:37:07,232
COMPLEMENTATION GROUP XPJ. HERE

812
00:37:07,232 --> 00:37:11,970
IS THE CLINICAL TEAM ON THEIR

813
00:37:11,970 --> 00:37:12,971
ANNUAL RETREAT WHERE THEY

814
00:37:12,971 --> 00:37:16,841
DISCUSS MATTERS OF INTEREST AND

815
00:37:16,841 --> 00:37:22,313
FUTURE WAYS OF HANDLING HP

816
00:37:22,313 --> 00:37:24,249
CLINICS IN THE FINAL TEN MINUTES

817
00:37:24,249 --> 00:37:28,586
I WILL TELL YOU BRIEFLY ABOUT

818
00:37:28,586 --> 00:37:32,423
THE (INAUDIBLE)

819
00:37:32,423 --> 00:37:33,324
MULTI-DISCIPLINARY CLINIC

820
00:37:33,324 --> 00:37:35,793
ESTABLISHED IN 2019 BY MY

821
00:37:35,793 --> 00:37:38,296
CLINICAL GENETICS COLLEAGUE.

822
00:37:38,296 --> 00:37:40,098
APPARENTLY WE HAVE 65 PATIENTS

823
00:37:40,098 --> 00:37:42,433
ON THE BOARD. .  THEY ARE SEEN

824
00:37:42,433 --> 00:37:44,903
BY THESE SPECIALISTS AND AGAIN

825
00:37:44,903 --> 00:37:46,871
I'M CONSULTANT SCIENTIST FOR

826
00:37:46,871 --> 00:37:51,309
THIS CLINIC.  IT IS IN RARE

827
00:37:51,309 --> 00:37:54,312
DISEASE CENTER SAINT THOMAS

828
00:37:54,312 --> 00:37:59,417
HOSPITAL IN LONDON. SO HERE IS A

829
00:37:59,417 --> 00:38:02,453
SUMMARY OF THE PATIENTS, 34

830
00:38:02,453 --> 00:38:05,256
CAUCASIAN PATIENTS WHICH ABOUT

831
00:38:05,256 --> 00:38:08,826
ONE-THIRD CSA AND TWO-THIRDS CSB

832
00:38:08,826 --> 00:38:10,662
IS SEEN IN SEVERAL OTHER

833
00:38:10,662 --> 00:38:14,899
STUDIES. WE HAVE 7 INDIVIDUALS

834
00:38:14,899 --> 00:38:20,805
WE CLASSIFY AS (INAUDIBLE)

835
00:38:20,805 --> 00:38:24,475
SYNDROME LIKE. WE HAVE 17 BE TTD

836
00:38:24,475 --> 00:38:27,712
MOST WHICH ARE MUTATED IN XPV

837
00:38:27,712 --> 00:38:33,618
BUT COUPLE IN TTDA, COUPLE IN

838
00:38:33,618 --> 00:38:35,386
TTN 1, WE HAVEN'T YET BEEN ABLE

839
00:38:35,386 --> 00:38:39,257
TO ASSIGN TO A PARTICULAR GENE.

840
00:38:39,257 --> 00:38:40,858
RECENTLY THE CLINIC STARTED

841
00:38:40,858 --> 00:38:43,061
TAKING ON BLOOM SYNDROME, NOT

842
00:38:43,061 --> 00:38:44,362
REALLY I'M NOT INVOLVE THIRD

843
00:38:44,362 --> 00:38:46,097
DEGREE IN THAT AND I WILL ONLY

844
00:38:46,097 --> 00:38:48,266
TALK ABOUT CS AND CS LIKE

845
00:38:48,266 --> 00:38:51,903
INDIVIDUALS TODAY.  SO FOR THOSE

846
00:38:51,903 --> 00:38:53,905
OF YOU NOT THAT FAMILIAR WITH

847
00:38:53,905 --> 00:38:57,075
COCAINE SYNDROME, HERE IS THE

848
00:38:57,075 --> 00:39:00,244
CLINICAL FEATURE GROWTH FAILURE

849
00:39:00,244 --> 00:39:03,681
CATARACTS, HEARING LOSS, PHOTO

850
00:39:03,681 --> 00:39:05,350
SENSITIVITY, DENTAL ISSUES

851
00:39:05,350 --> 00:39:10,188
SPEECH ISSUESS. SENSITIVITY TO V

852
00:39:10,188 --> 00:39:12,223
WHICH WE DETECT USING THE ROS

853
00:39:12,223 --> 00:39:17,195
TEST, ROS FOR RECOVERY OF RNA

854
00:39:17,195 --> 00:39:20,298
SYNTHESSYNTHESIS. WIDE SPECTRUMF

855
00:39:20,298 --> 00:39:22,066
PHENOTYPES, MOST OF THEM SADLY

856
00:39:22,066 --> 00:39:24,235
DIE MANY THE FIRST OR SECOND

857
00:39:24,235 --> 00:39:27,305
DECADE, IT IS A VERY SEVERE

858
00:39:27,305 --> 00:39:30,074
DISORDEORDER. THERE ARE ONE OR O

859
00:39:30,074 --> 00:39:31,409
EXCEPTIONS, THIS IS A LADY THAT

860
00:39:31,409 --> 00:39:37,482
CAME TO CLINIC AGE 52 WITH

861
00:39:37,482 --> 00:39:39,584
COCKYNE SYNDROME. THE PROTRUDING

862
00:39:39,584 --> 00:39:41,252
TEETH AND DEEP SET EYES.  SHE

863
00:39:41,252 --> 00:39:45,823
HAS A MUTATION HETEROZYGOUS 11

864
00:39:45,823 --> 00:39:47,692
TRUNCATION MUTATION. AND

865
00:39:47,692 --> 00:39:50,528
INTERESTINGLY THE OTHER ONE IS A

866
00:39:50,528 --> 00:39:53,665
SPLICE MUTATION. SO WE WONDER IF

867
00:39:53,665 --> 00:39:55,900
MAKING A SMALL AMOUNT OF NORMAL

868
00:39:55,900 --> 00:39:58,970
PROTEIN. HOWEVER, WHEN WE LOOK

869
00:39:58,970 --> 00:40:01,773
IN OUR RS TEST WE DON'T SEE ANY

870
00:40:01,773 --> 00:40:04,208
DIFFERENCE BETWEEN THE UV

871
00:40:04,208 --> 00:40:07,111
SENSITIVITY OF HER CELLS AN

872
00:40:07,111 --> 00:40:09,881
THOSE OF THE MUCH YOUNGER

873
00:40:09,881 --> 00:40:11,149
PATIENTS WITH MORE NORMAL

874
00:40:11,149 --> 00:40:20,358
SYMPTOMS AT A YOUNG AGE. SO FEW

875
00:40:20,358 --> 00:40:22,794
SLIDES ABOUT COCKAYNE LIKE

876
00:40:22,794 --> 00:40:24,362
PATIENTS. THE FIRST WAS THIS

877
00:40:24,362 --> 00:40:29,400
YOUNG LADY WHO HAD MANY COCKAYNP

878
00:40:29,400 --> 00:40:32,003
FEATURES DELAYED MOTOR

879
00:40:32,003 --> 00:40:33,371
DEVELOPMENT, THIS MORPHIC

880
00:40:33,371 --> 00:40:35,039
FEATURE -- DISMORE IF I CAN

881
00:40:35,039 --> 00:40:36,941
FEATURES DEEP SET EYES BUT SHE

882
00:40:36,941 --> 00:40:38,409
WASN'T PHOTOSENSITIVE. WHEN WE

883
00:40:38,409 --> 00:40:40,411
DID THE ROS TEST IT WAS

884
00:40:40,411 --> 00:40:43,848
COMPLETELY NORMAL. SO IN

885
00:40:43,848 --> 00:40:45,316
COLLABORATION BETWEEN

886
00:40:45,316 --> 00:40:49,721
(INAUDIBLE) LAB, AND JEGGO LAB

887
00:40:49,721 --> 00:40:52,857
AND OUR LAB DID WHOLE EXOSOME

888
00:40:52,857 --> 00:40:53,891
SEQUENCING AND FOUND MUTATIONS

889
00:40:53,891 --> 00:40:58,563
IN THE XRCC 4 GENE, COMPOUND

890
00:40:58,563 --> 00:40:59,564
HETEROZYGOTES LEADING TO

891
00:40:59,564 --> 00:41:03,501
TRUNCATIONS.  IF YOU LOOK AT

892
00:41:03,501 --> 00:41:05,002
WESTERN BLOT USING ANTIBODY

893
00:41:05,002 --> 00:41:08,940
DIRECT RCC 4 HERE IS FOUND IN

894
00:41:08,940 --> 00:41:10,975
NORMAL INDIVIDUALS, ANOTHER --

895
00:41:10,975 --> 00:41:13,177
SORRY HERE IS BAND IN NORMAL

896
00:41:13,177 --> 00:41:16,514
INDIVIDUALS, BUT IN SIMILAR

897
00:41:16,514 --> 00:41:19,350
AMOUNT EXTRACT FROM THIS

898
00:41:19,350 --> 00:41:23,721
INDIVIDUAL YOU SEE NO TRACE OF

899
00:41:23,721 --> 00:41:26,991
XRCC 4. XRCC 4 IS KNOWN

900
00:41:26,991 --> 00:41:28,593
ESSENTIAL GENE SO WE SUSPECT

901
00:41:28,593 --> 00:41:33,431
THERE MUST BE A SMALL AMOUNT AND

902
00:41:33,431 --> 00:41:34,999
WE KNOW IT IS POSSIBLE TO DETECT

903
00:41:34,999 --> 00:41:37,468
A VERY SMALL AMOUNT LESS THAN 5%

904
00:41:37,468 --> 00:41:40,671
OF XRCC 4 BUT THAT SEEMED

905
00:41:40,671 --> 00:41:42,106
SUFFICIENT FOR THIS YOUNG LADY

906
00:41:42,106 --> 00:41:44,609
TO SURVIVE WITH THESE -- UNTIL

907
00:41:44,609 --> 00:41:47,211
SHE WAS 26 OR 27 WHEN SHE SADLY

908
00:41:47,211 --> 00:41:55,219
DIED A COUPLE OF YEARS AGO. SO

909
00:41:55,219 --> 00:41:57,054
TWO -- ONE OTHER REMARKABLE

910
00:41:57,054 --> 00:42:01,826
POINT WE PUBLISHED THIS WORK IN

911
00:42:01,826 --> 00:42:06,998
2015 UP TO 2014, NO XRCC 4

912
00:42:06,998 --> 00:42:10,301
PATIENTS IDENTIFIED OR REPORTED

913
00:42:10,301 --> 00:42:14,739
IN 2014, 15, THERE WERE 6 PAPERS

914
00:42:14,739 --> 00:42:15,807
REPORTING DRCC 4 PATIENTS

915
00:42:15,807 --> 00:42:17,775
INCLUDING ONE FROM ANDREW

916
00:42:17,775 --> 00:42:21,345
JACKSON'S LAB IN EKNBORO. AND

917
00:42:21,345 --> 00:42:23,014
AGAIN, IT WAS ANOTHER EXAMPLE OF

918
00:42:23,014 --> 00:42:24,415
EVERYTHING HAPPENING THE SAME

919
00:42:24,415 --> 00:42:26,517
YEAR. I HAVEN'T BEEN ABLE TO

920
00:42:26,517 --> 00:42:29,120
FIND ANY FURTHER REPORTS OF XRCC

921
00:42:29,120 --> 00:42:37,962
4 PATIENTS. SINCE 2015. TWO

922
00:42:37,962 --> 00:42:39,230
(INAUDIBLE) TURNED UP AT OUR

923
00:42:39,230 --> 00:42:41,699
CLINIC. THIS IS ONE OF THEM. THE

924
00:42:41,699 --> 00:42:44,068
MOST DRAMATIC FEATURE IS THIS

925
00:42:44,068 --> 00:42:46,370
SEVERE GROWTH DELAY. THIS YOUNG

926
00:42:46,370 --> 00:42:48,773
MAN HERE, HE'S FIVE YEARS OLD.

927
00:42:48,773 --> 00:42:51,642
AND YOU CAN SEE HERE HE IS

928
00:42:51,642 --> 00:42:57,815
ABSOLUTELY TINY. COGNITIVE

929
00:42:57,815 --> 00:42:59,951
DEVELOPMENT DELAY BUT HE RUNS

930
00:42:59,951 --> 00:43:01,719
AROUND QUITE HAPPILY, HE DOESN'T

931
00:43:01,719 --> 00:43:07,592
SPEAK BUT HE HAS THESE COCKAYNE

932
00:43:07,592 --> 00:43:09,393
FEETURES YOU CAN SEE THE

933
00:43:09,393 --> 00:43:11,429
COMPOUND HETERO ZYGOTES AND THE

934
00:43:11,429 --> 00:43:12,029
PREVIOUS PATIENT YOU MENTIONED

935
00:43:12,029 --> 00:43:16,234
AND THIS YOUNG MAN ARE SENSITIVE

936
00:43:16,234 --> 00:43:18,436
TO IONIZING RADIATION AND

937
00:43:18,436 --> 00:43:20,504
DEFICIENT IN DOUBLE STRAND BREAK

938
00:43:20,504 --> 00:43:24,375
REPAIR AS YOU EXPECT BECAUSE

939
00:43:24,375 --> 00:43:26,677
XRCC 4 IS CO-FACTOR FOR DNA

940
00:43:26,677 --> 00:43:28,980
LIGASE KNOWN TO BE INVOLVED IN

941
00:43:28,980 --> 00:43:33,084
DOUBLE STRAND BREAK REPAIR FOR

942
00:43:33,084 --> 00:43:34,752
MANY YEARS. THIS IS SURVIVAL

943
00:43:34,752 --> 00:43:36,854
AFTER IONIZING RADIATION NORMAL

944
00:43:36,854 --> 00:43:38,456
INDIVIDUALS AND HERE IS PATIENT.

945
00:43:38,456 --> 00:43:41,893
THIS WORK IS DONE BY MY

946
00:43:41,893 --> 00:43:46,898
COLLEAGUE LISA WOODBONE. SO

947
00:43:46,898 --> 00:43:51,869
PETER CANE'S LAB IN IN FLORIDA

948
00:43:51,869 --> 00:43:55,206
HAD SHOWN THEY ALSO HAD SOME

949
00:43:55,206 --> 00:43:57,108
COCKAYNE LIKE PATIENTS AND

950
00:43:57,108 --> 00:44:02,046
PICKED ORAL 2 MUTATIONS

951
00:44:02,046 --> 00:44:03,080
(INAUDIBLE) WE HAVE HALF DOZEN

952
00:44:03,080 --> 00:44:04,448
PATIENTS BUT WE THOUGHT LOOKED

953
00:44:04,448 --> 00:44:07,451
VERY MUCH LIKE COCKAYNE PATIENTS

954
00:44:07,451 --> 00:44:11,522
BUT NORMAL ROS AND DIDN'T HAVE

955
00:44:11,522 --> 00:44:14,058
MUTATIONS IN THE CSA OR CSB

956
00:44:14,058 --> 00:44:15,960
GENES SO WE SENT THE CELLS TO

957
00:44:15,960 --> 00:44:18,296
PETER'S LAB AND HE FOUND THAT

958
00:44:18,296 --> 00:44:20,498
THREE OF THEM HAD MUTATIONS IN

959
00:44:20,498 --> 00:44:23,935
THE SAME GENE, MORC 2. SO HERE

960
00:44:23,935 --> 00:44:27,371
IS A COUPLE OF SIBLINGS THEY

961
00:44:27,371 --> 00:44:29,407
FOUND MUTATED IN THAT GENE. SO

962
00:44:29,407 --> 00:44:31,409
THE CLINICAL FEATURES AGAIN,

963
00:44:31,409 --> 00:44:35,079
SIMILAR FOR COCKAYNE, SHORT

964
00:44:35,079 --> 00:44:37,481
STATURE GATE DISTURBANCE

965
00:44:37,481 --> 00:44:39,250
ABNORMAL TENDON REFLEXES,

966
00:44:39,250 --> 00:44:40,217
TREMORS AND INTELLECTUAL

967
00:44:40,217 --> 00:44:43,888
DISABILITY. NO MUTATION, CS

968
00:44:43,888 --> 00:44:47,992
GENES NORMAL RECOVERY OF RS AT

969
00:44:47,992 --> 00:44:52,797
THE U -- AFTER UV. THEY HAD DE

970
00:44:52,797 --> 00:44:56,467
NOVO HETEROZYGOUS MUTATION IN

971
00:44:56,467 --> 00:44:58,135
MOCR 2 GENE KNOWN TO BE DOMINANT

972
00:44:58,135 --> 00:44:59,236
SO THESE TWO INDIVIDUALS

973
00:44:59,236 --> 00:45:02,273
MUTATION IS MISSENSE MUTATION

974
00:45:02,273 --> 00:45:06,577
ALANINE TO AND TORR SCENE TO 3

975
00:45:06,577 --> 00:45:10,715
ANINE. WHAT IS MORC 2?

976
00:45:10,715 --> 00:45:12,950
TRANSCRIPT -- ROLES IN

977
00:45:12,950 --> 00:45:16,387
TRANSCRIPTION REGRESSION, DNA

978
00:45:16,387 --> 00:45:17,888
DAMAGE RESPONSE IN METABOLISM.

979
00:45:17,888 --> 00:45:20,191
IT IS ASSOCIATED WITH TWO OR

980
00:45:20,191 --> 00:45:24,061
THREE OTHER DIFFERENT DISORDERS 

981
00:45:24,061 --> 00:45:27,398
SO THIS IS FROM A REVIEW LAST

982
00:45:27,398 --> 00:45:32,069
YEAR SHOWING THE ROLES OF MORC 2

983
00:45:32,069 --> 00:45:33,838
HOW IT IS IMPLICATED IN DNA

984
00:45:33,838 --> 00:45:36,107
DAMAGE RESPONSE. THE DIMERIZED

985
00:45:36,107 --> 00:45:39,343
FORM GETS PHOSPHORYLATED BY THE

986
00:45:39,343 --> 00:45:42,179
ATM DNA DOUBLE STRAND BREAK DNA

987
00:45:42,179 --> 00:45:44,682
DAMAGE RESPONSE. IT SEEMS TO BE

988
00:45:44,682 --> 00:45:47,418
NEEDED TO ASSIST DNA REPAIR.

989
00:45:47,418 --> 00:45:51,889
ALSO SEEMS TO HAVE A ROLE IN

990
00:45:51,889 --> 00:45:53,257
MORC 1 STABILITY AND INDICATED

991
00:45:53,257 --> 00:45:58,062
IN DEPHOSPHORYLATION OF

992
00:45:58,062 --> 00:46:01,732
PHOSPHORYLATED HISTONES. NOT A

993
00:46:01,732 --> 00:46:02,733
GREAT DEAL WAS KNOWN ABOUT IT

994
00:46:02,733 --> 00:46:04,702
AND HOW IT WORKED AND SEEMED A

995
00:46:04,702 --> 00:46:08,739
FRUITFUL AREA FOR FURTHER

996
00:46:08,739 --> 00:46:12,810
RESEARCH. SUMMARIZING THE

997
00:46:12,810 --> 00:46:15,112
COCKAYNE SYNDROME CLINIC,

998
00:46:15,112 --> 00:46:17,448
CURRENT CS PATIENTS CURRENTLY

999
00:46:17,448 --> 00:46:18,716
VISITING A WIDE VARIETY OF

1000
00:46:18,716 --> 00:46:22,486
PHENOTYPE INCLUDING A

1001
00:46:22,486 --> 00:46:24,021
52-YEAR-OLD. UNFORTUNATELY

1002
00:46:24,021 --> 00:46:26,991
UNLIKE WITH XP NO CLEAR GENOTYPE

1003
00:46:26,991 --> 00:46:29,360
PHENOTYPE RELATIONSHIP IN THOSE

1004
00:46:29,360 --> 00:46:31,929
CASES. WE FOUND THIS OVER THE

1005
00:46:31,929 --> 00:46:34,765
YEARS WITH MANY COCKAYNE

1006
00:46:34,765 --> 00:46:35,900
PATIENTS AND IT IS CAUSE OF

1007
00:46:35,900 --> 00:46:39,336
FRUSTRATION TO US. WE FOUND THE

1008
00:46:39,336 --> 00:46:40,171
SEVERAL INTERESTING CASES OF CS

1009
00:46:40,171 --> 00:46:43,240
LIKE FEATURES WITH MUTATIONS IN

1010
00:46:43,240 --> 00:46:47,678
UNEXPECTED DNA REPAIR GENES.  SO

1011
00:46:47,678 --> 00:46:49,914
HERE IS CS CLINICAL TEAM AGAIN

1012
00:46:49,914 --> 00:46:54,518
ON THEIR ANNUAL RETREAT TO

1013
00:46:54,518 --> 00:46:56,187
(INAUDIBLE) THIS WAS WAS JUST A

1014
00:46:56,187 --> 00:46:58,089
COUPLE OF WEEKS AGO. I THINK I

1015
00:46:58,089 --> 00:47:00,024
HAVE ACKNOWLEDGED ALL THE

1016
00:47:00,024 --> 00:47:02,326
PARTICIPANTS, ALL MY

1017
00:47:02,326 --> 00:47:03,360
COLLABORATORS, MY ROLE IN MUCH

1018
00:47:03,360 --> 00:47:06,163
OF WHAT I TALKED ABOUT HAVE BEEN

1019
00:47:06,163 --> 00:47:07,698
VERY MINIMAL BUT I THINK I WILL

1020
00:47:07,698 --> 00:47:09,533
LEAVE IT THERE AND TAKE ANY

1021
00:47:09,533 --> 00:47:18,476
QUESTIONS, THANK YOU VERY MUCH. 

1022
00:47:18,476 --> 00:47:19,944
>> THANK YOU, PROFESSOR
LEHMANN

1023
00:47:19,944 --> 00:47:22,980
FOR THE WONDERFUL TALK, IT IS

1024
00:47:22,980 --> 00:47:27,218
SUCH AN OVERVIEW FOR THE XP AND

1025
00:47:27,218 --> 00:47:28,552
FOR THE AUDIENCES PLEASE TYPE IN

1026
00:47:28,552 --> 00:47:31,222
YOUR QUESTION IN THE CHAT BOX.

1027
00:47:31,222 --> 00:47:32,656
AND THEN WE WILL ELABORATE OVER

1028
00:47:32,656 --> 00:47:38,028
HERE. WHILE OTHERS ARE TYPING IN

1029
00:47:38,028 --> 00:47:40,131
QUESTIONS, I HAVE A GENERAL

1030
00:47:40,131 --> 00:47:42,666
QUESTION OVER HERE. SO FOR THE

1031
00:47:42,666 --> 00:47:44,101
XP SEEMS LIKE THERE ARE VARIOUS

1032
00:47:44,101 --> 00:47:48,839
TYPE OF MUTATION. SO DO THEY

1033
00:47:48,839 --> 00:47:51,909
OFTEN COME WITH INHERITED

1034
00:47:51,909 --> 00:47:57,848
DISEASE OR LIKE SOMATIC DISEASE

1035
00:47:57,848 --> 00:47:59,083
LIKE (INAUDIBLE)?

1036
00:47:59,083 --> 00:48:00,718
>> BP ARE INHERITED, THE

1037
00:48:00,718 --> 00:48:04,688
MUTATIONS ARE INHERITED. THE

1038
00:48:04,688 --> 00:48:06,457
SOMATIC MUTATIONS GENERATED AS A

1039
00:48:06,457 --> 00:48:10,294
FUNCTION -- AS BY EXPOSURE TO UV

1040
00:48:10,294 --> 00:48:12,696
WHAT GENERATE THE (INAUDIBLE)

1041
00:48:12,696 --> 00:48:13,964
BUT THE INITIAL MUTATIONS ARE

1042
00:48:13,964 --> 00:48:15,399
INHERITED YES.

1043
00:48:15,399 --> 00:48:25,943
>> THANK YOU. I THINK DR.
BOHR,

1044
00:48:26,744 --> 00:48:27,778
ARE YOU TALKING? YOU ARE ON

1045
00:48:27,778 --> 00:48:31,215
MUTE. 

1046
00:48:31,215 --> 00:48:34,785
>> JUST A WONDERFUL TALK.
THANK

1047
00:48:34,785 --> 00:48:37,054
YOU FOR THIS. ONE QUESTION I

1048
00:48:37,054 --> 00:48:39,557
HAD, IT IS REALLY INTERESTING

1049
00:48:39,557 --> 00:48:43,127
WITH THIS LOW LEVEL XPA BEING

1050
00:48:43,127 --> 00:48:46,964
SUFFICIENT TO AVOID

1051
00:48:46,964 --> 00:48:47,765
NEURODEGENERATION, IN THOSE

1052
00:48:47,765 --> 00:48:50,768
PATIENTS WAS IT THE LOWEST LEVEL

1053
00:48:50,768 --> 00:48:55,339
WAS 5% OR WAS IT AN AVERAGE 5%?

1054
00:48:55,339 --> 00:48:59,543
IS IT LIKE WE CAN SAY THAT

1055
00:48:59,543 --> 00:49:03,414
MINIMALLY 5% IS ENOUGH OR CAN WE

1056
00:49:03,414 --> 00:49:05,015
SAY AVERAGE 5% IS ENOUGH?

1057
00:49:05,015 --> 00:49:10,988
>> NO. OKAY. SO I THINK 5%
OF --

1058
00:49:10,988 --> 00:49:13,824
I THINK WE CAN SAY THAT 5% OF

1059
00:49:13,824 --> 00:49:16,894
THE XPA PROTEIN IS ENOUGH. THE

1060
00:49:16,894 --> 00:49:21,432
LEVEL OF UVS I WOULD SAY IS NOT

1061
00:49:21,432 --> 00:49:23,334
-- WE DO A KIND OF QUICK AND

1062
00:49:23,334 --> 00:49:25,970
DIRTY UDS WHICH IS NOT

1063
00:49:25,970 --> 00:49:27,304
COMPLETELY QUANTITATIVE BUT FROM

1064
00:49:27,304 --> 00:49:29,006
THAT I WOULD SAY THE LEVEL OF

1065
00:49:29,006 --> 00:49:31,775
UDS WAS BETWEEN 5 AND 15% AND

1066
00:49:31,775 --> 00:49:32,943
THERE MAYBE SOME VARIABILITY

1067
00:49:32,943 --> 00:49:37,948
THERE.

1068
00:49:37,948 --> 00:49:40,284
>> REALLY INTERESTING.
OKAY.

1069
00:49:40,284 --> 00:49:43,287
NOW, THERE'S SOME QUESTIONS IN

1070
00:49:43,287 --> 00:49:45,089
THE CHAT

1071
00:49:45,089 --> 00:49:46,490
>> SO (INAUDIBLE) SAID
THANKS

1072
00:49:46,490 --> 00:49:47,625
FOR THE OUTSTANDING TALK AND

1073
00:49:47,625 --> 00:49:50,694
SHARING YOUR RECENT P 52 DATA.

1074
00:49:50,694 --> 00:49:54,531
SINCE DDB 2 KNOCKOUT MICE GET

1075
00:49:54,531 --> 00:49:56,967
INTERNAL TUMORS HAVE YOU SEEN

1076
00:49:56,967 --> 00:49:59,737
INTERNAL TUMORS IN XPE PATIENTS?

1077
00:49:59,737 --> 00:50:04,608
>> INTERNAL TUMORS, NO.
THEY GET

1078
00:50:04,608 --> 00:50:06,944
-- I THINK KEN'S GROUP HAVE

1079
00:50:06,944 --> 00:50:10,014
REPORTED THIS AS WELL. BECAUSE

1080
00:50:10,014 --> 00:50:11,548
THEY ARE RELATIVELY MILD THEY

1081
00:50:11,548 --> 00:50:14,385
ARE NOT DIAGNOSED UNTIL LATE SO

1082
00:50:14,385 --> 00:50:16,287
BY THE TIME THEY ARE DIAGNOSED

1083
00:50:16,287 --> 00:50:19,189
THEY ACCUMULATED LOTS OF

1084
00:50:19,189 --> 00:50:21,992
MUTATIONS. SO LATER ON IN LIFE

1085
00:50:21,992 --> 00:50:25,796
30s, 40s AND 50s THEY GET

1086
00:50:25,796 --> 00:50:28,832
LOCKED IN SOMETIMES HUNDREDS OF

1087
00:50:28,832 --> 00:50:30,868
SKIN CANCER BUT WE HAVEN'T HAD

1088
00:50:30,868 --> 00:50:35,806
ANY INTERNAL TUMORS, PRETTY SURE

1089
00:50:35,806 --> 00:50:36,507
NO INTERNAL TUMORS.

1090
00:50:36,507 --> 00:50:39,276
>> YES. I WAS JUST TALKING

1091
00:50:39,276 --> 00:50:40,811
YESTERDAY WITH A XPE PATIENT IN

1092
00:50:40,811 --> 00:50:47,151
THEIR '60s. SHE DEVELOPED

1093
00:50:47,151 --> 00:50:50,387
THYROID CANCER. INTERESTINGLY

1094
00:50:50,387 --> 00:50:53,123
ENOUGH (INAUDIBLE) TAMORA HAD

1095
00:50:53,123 --> 00:50:55,092
HEARD ABOUT THYROID CANCERS IN

1096
00:50:55,092 --> 00:50:56,593
XP PATIENTS IN THE MIDDLE EAST

1097
00:50:56,593 --> 00:50:57,628
AND STARTED CALLING THE PATIENTS

1098
00:50:57,628 --> 00:51:00,397
AND ASKING THEM TO GET THYROID

1099
00:51:00,397 --> 00:51:02,633
ULTRA SOUNDS AND TURNED OUT SHE

1100
00:51:02,633 --> 00:51:05,269
HAD CANCER, IT WAS TOTALLY

1101
00:51:05,269 --> 00:51:07,204
UNSUSPECTED. SHE DID HAVE THAT.

1102
00:51:07,204 --> 00:51:09,807
BUT SIMILARLY SHE ALSO HAD

1103
00:51:09,807 --> 00:51:16,080
SEVERAL HUNDRED SKIN CANCERS. 

1104
00:51:16,080 --> 00:51:17,715
ANOTHER COMMENT, WE PUBLISHED A

1105
00:51:17,715 --> 00:51:21,618
PAPER RECENTLY, IN THE LAB DID A

1106
00:51:21,618 --> 00:51:23,954
SURVEY OF THE LITERATURE AND THE

1107
00:51:23,954 --> 00:51:26,857
PATIENTS WE HAD -- WHO HAD

1108
00:51:26,857 --> 00:51:28,125
METASTATIC CANCER WITH XP AND

1109
00:51:28,125 --> 00:51:29,860
THEY WERE TREATED WITH IMMUNE

1110
00:51:29,860 --> 00:51:32,763
CHECK POINT INHERES TO. . BEHAD

1111
00:51:32,763 --> 00:51:34,064
SEVERAL DOZEN AND THEY ALL

1112
00:51:34,064 --> 00:51:38,435
RESPONDED VERY WELL.  

1113
00:51:38,435 --> 00:51:39,670
INDEPENDENT OF THE PARTICULAR

1114
00:51:39,670 --> 00:51:42,439
MUTATIONS IN THEIR TUMORS.

1115
00:51:42,439 --> 00:51:45,843
>> (INAUDIBLE) THOSE WERE

1116
00:51:45,843 --> 00:51:46,310
SECs?

1117
00:51:46,310 --> 00:51:49,313
>> A VARIETY OF DIFFERENT
ONES. 

1118
00:51:49,313 --> 00:51:53,817
>> OKAY.

1119
00:51:53,817 --> 00:51:57,354
>> HERE IS A QUESTION FROM

1120
00:51:57,354 --> 00:51:59,456
DMITRI. YOU MENTIONED MELANOMA

1121
00:51:59,456 --> 00:52:03,327
IN XP POSITIVE INDIVIDUAL HAS

1122
00:52:03,327 --> 00:52:04,795
HUNDREDS OF THOUSANDS OF

1123
00:52:04,795 --> 00:52:08,432
AMYATIONS IN UV LIGHT MOTIF.

1124
00:52:08,432 --> 00:52:11,201
WHAT IS THE CURRENT FEUD WITH

1125
00:52:11,201 --> 00:52:16,774
ALL THE ORIGIN OF SUCH

1126
00:52:16,774 --> 00:52:18,008
HYPERMUTATION?

1127
00:52:18,008 --> 00:52:21,645
>> I GUESS THAT IS WHAT
YOU

1128
00:52:21,645 --> 00:52:24,515
PREDICT. BECAUSE NER OR XP

1129
00:52:24,515 --> 00:52:29,853
VARIANTS TLS IS DEFECTIVE,

1130
00:52:29,853 --> 00:52:34,558
SHOWED EARLY VERONICA'S GROUP

1131
00:52:34,558 --> 00:52:35,759
SHOWING HYPERMUTABILITY SO I

1132
00:52:35,759 --> 00:52:36,860
THINK THAT IS EXACTLY WHAT YOU

1133
00:52:36,860 --> 00:52:40,464
WOULD PREDICT FROM AN XP

1134
00:52:40,464 --> 00:52:41,899
INDIVIDUINDIVIDUAL. THAT SHE WOE

1135
00:52:41,899 --> 00:52:47,438
LOTS OF MUTATIONS. 

1136
00:52:47,438 --> 00:52:52,543
>> CAN I ASK QUICKLY, THE
MORC 2

1137
00:52:52,543 --> 00:52:54,545
MUTATION ONLY SEEN IN CS LIKE

1138
00:52:54,545 --> 00:52:56,046
CONDITIONS OR OTHER DNA REPAIR

1139
00:52:56,046 --> 00:52:59,316
DISEASES?

1140
00:52:59,316 --> 00:53:01,485
>> SEEN IN OTHER DISEASES
BUT

1141
00:53:01,485 --> 00:53:03,487
NOT OTHER DNA REPAIR DISEASES.

1142
00:53:03,487 --> 00:53:06,790
>> OKAY. WHAT DISEASES IS
IT

1143
00:53:06,790 --> 00:53:08,525
SEEN IN?

1144
00:53:08,525 --> 00:53:12,896
>> I THINK IT IS --

1145
00:53:12,896 --> 00:53:15,566
>> TS 1 --

1146
00:53:15,566 --> 00:53:18,135
>> (INAUDIBLE) 2 DISEASE.

1147
00:53:18,135 --> 00:53:19,837
>> YES.

1148
00:53:19,837 --> 00:53:23,474
>> IF YOU CHECK OUT THAT
REVIEW

1149
00:53:23,474 --> 00:53:26,677
YOU CAN GET ALL THE INFORMATION

1150
00:53:26,677 --> 00:53:31,014
ON THE (INAUDIBLE) 2022. IT IS

1151
00:53:31,014 --> 00:53:35,185
THE MUTATIONS SEEM TO BE DE NOVO

1152
00:53:35,185 --> 00:53:38,889
MUTATIONS IS DOMINANT MUTATION. 

1153
00:53:38,889 --> 00:53:41,792
>> DMITRI HAS A FOLLOW-UP
POINT

1154
00:53:41,792 --> 00:53:43,794
SAYING HIS QUESTION IS ABOUT XP

1155
00:53:43,794 --> 00:53:46,897
WILD TYPE PATIENTS. 

1156
00:53:46,897 --> 00:53:50,033
>> SORRY --

1157
00:53:50,033 --> 00:53:52,736
>> I THINK HE'S TALKING

1158
00:53:52,736 --> 00:53:54,371
MELANOMAS IN IN INDIVIDUAL WHOSE

1159
00:53:54,371 --> 00:53:55,239
ARE WILD TYPE FOR XP.

1160
00:53:55,239 --> 00:54:00,177
>> OKAY. SO THE QUESTION
IS, THE

1161
00:54:00,177 --> 00:54:02,679
POINT IS THEY'RE VERY HIGH

1162
00:54:02,679 --> 00:54:08,752
LEVELS OF MUTATIONS, (INAUDIBLE)

1163
00:54:08,752 --> 00:54:11,522
IS CERTAINLY THE QUESTION?

1164
00:54:11,522 --> 00:54:15,926
>> HIS QUESTION IS
PROBABLY XP

1165
00:54:15,926 --> 00:54:18,128
WILD TYPE MELANOMA INDIVIDUAL

1166
00:54:18,128 --> 00:54:20,664
HAVE HUNDREDS OF CELLS IN UV

1167
00:54:20,664 --> 00:54:23,967
LIGHT MOTIF. SO WHAT IS THE VIEW

1168
00:54:23,967 --> 00:54:25,936
ON THE ON ORIGIN OF SUCH

1169
00:54:25,936 --> 00:54:27,371
HYPERMUTATION LOAD?

1170
00:54:27,371 --> 00:54:30,574
>> SORRY I MISUNDERSTOOD.
WE ARE

1171
00:54:30,574 --> 00:54:33,677
TALKING NORMAL INDIVIDUALS HAVE

1172
00:54:33,677 --> 00:54:35,979
-- WHO HAVE VERY HIGH LEVELS OF

1173
00:54:35,979 --> 00:54:37,748
MUTATIONS IN THEIR MELANOMA, I

1174
00:54:37,748 --> 00:54:42,085
GUESS THAT IS THE QUESTION. NOT

1175
00:54:42,085 --> 00:54:43,487
SURE I CAN GIVE A SENSIBLE

1176
00:54:43,487 --> 00:54:47,024
ANSWER TO THAT. SORRY. I DON'T

1177
00:54:47,024 --> 00:54:49,092
KNOW IF KEN OR ANYONE ELSE CAN

1178
00:54:49,092 --> 00:54:54,631
--

1179
00:54:54,631 --> 00:54:57,768
>> IT IS AN ARGUMENT THAN
LINKS

1180
00:54:57,768 --> 00:55:00,938
MELANOMAS TO UV EXPOSURE. 

1181
00:55:00,938 --> 00:55:04,241
>> I LIKE TO POINT OUT

1182
00:55:04,241 --> 00:55:06,677
(INAUDIBLE) ATTENDING THIS

1183
00:55:06,677 --> 00:55:09,146
LECTURE TODAY H.

1184
00:55:09,146 --> 00:55:13,517
>> GREAT.

1185
00:55:13,517 --> 00:55:20,257
>> ALSO THE YOU MENTION XP
AND

1186
00:55:20,257 --> 00:55:24,695
COCKAYNE WITH MUSCULAR DYSTRO 

1187
00:55:24,695 --> 00:55:25,662
DYSTROPHY, WE HAVE SEEN

1188
00:55:25,662 --> 00:55:27,798
MUTATIONS WITH XP AND

1189
00:55:27,798 --> 00:55:30,901
(INAUDIBLE) IN COCKAYNE

1190
00:55:30,901 --> 00:55:32,569
SYNDROME, IT GETS TRICKY

1191
00:55:32,569 --> 00:55:33,704
CLINICALLY DISTINGUISHING AMONG

1192
00:55:33,704 --> 00:55:34,404
THETHEM.

1193
00:55:34,404 --> 00:55:35,539
>> WE HAVE WORKING ON THAT
FOR

1194
00:55:35,539 --> 00:55:36,373
YEARS. 

1195
00:55:36,373 --> 00:55:39,676
>> YES.

1196
00:55:39,676 --> 00:55:40,711
>> THERE IS ANOTHER
QUESTION IN

1197
00:55:40,711 --> 00:55:46,083
THE CHAT. FROM (INAUDIBLE). MANY

1198
00:55:46,083 --> 00:55:48,352
XP PATIENTS BENEFIT FROM ICB

1199
00:55:48,352 --> 00:55:50,053
THERAPY, IS THIS THE TIME TO

1200
00:55:50,053 --> 00:55:51,121
DEVELOP AN INTERNATIONAL

1201
00:55:51,121 --> 00:55:52,589
CLINICAL GUIDELINE BASED ON

1202
00:55:52,589 --> 00:55:55,993
PRIOR RESULTS?

1203
00:55:55,993 --> 00:55:59,229
>> SORRY I DON'T KNOW WHAT
ICB

1204
00:55:59,229 --> 00:55:59,796
IS. CAN --

1205
00:55:59,796 --> 00:56:01,531
>> IMMUNE CHECK POINT
BLOCKADE.

1206
00:56:01,531 --> 00:56:12,042
>> OKAY. SORRY. YES. SURE.
ANY

1207
00:56:17,514 --> 00:56:18,882
INTERNATIONAL COLLABORATION WITH

1208
00:56:18,882 --> 00:56:26,890
PATIENTS WOULD BE VERY USEFUL.

1209
00:56:26,890 --> 00:56:28,825
>> LAST CHANCE FOR PEOPLE
TO PUT

1210
00:56:28,825 --> 00:56:32,796
QUESTIONS IN THE CHAT.  OKAY. WE

1211
00:56:32,796 --> 00:56:35,999
HAVE SOME QUESTION FROM

1212
00:56:35,999 --> 00:56:36,967
(INAUDIBLE). THANKS FOR THIS

1213
00:56:36,967 --> 00:56:40,704
NICE TALK.  WHILE ANALYZING DATA

1214
00:56:40,704 --> 00:56:43,240
FOR ATYPICAL FORM OF XP PATIENTS

1215
00:56:43,240 --> 00:56:45,275
I FIND VARIANTS IN GENES RELATED

1216
00:56:45,275 --> 00:56:47,477
TO NER BUT NOT THE KNOWN GENES

1217
00:56:47,477 --> 00:56:49,279
BEING SO FAR REPORTED FOR XP.

1218
00:56:49,279 --> 00:56:51,882
BUT I'M HESITATING BEFORE

1219
00:56:51,882 --> 00:56:52,783
PUBLICATION. SO THANK YOU

1220
00:56:52,783 --> 00:56:54,217
BECAUSE WITH THIS NEW GROUP WE

1221
00:56:54,217 --> 00:56:58,055
CAN NOW EXPECT NEW GENES IN THE

1222
00:56:58,055 --> 00:57:00,424
NER PATH BAY, EVEN OTHER

1223
00:57:00,424 --> 00:57:02,959
PATHWAYS RELATED TO DNA REPAIR.

1224
00:57:02,959 --> 00:57:04,961
MY QUESTION IS TO WHAT EXTENT

1225
00:57:04,961 --> 00:57:07,397
CAN WE BE CONFIDENT IN REPORTING

1226
00:57:07,397 --> 00:57:09,066
NEW GENES ESPECIALLY WHEN THE

1227
00:57:09,066 --> 00:57:11,201
ONLY PROOF I HAVE IS IN SILICO

1228
00:57:11,201 --> 00:57:15,038
FINDINGS?

1229
00:57:15,038 --> 00:57:18,375
>> SO THERE IS A PROBLEM
THEN

1230
00:57:18,375 --> 00:57:23,180
YOU CAN ONLY BE REALLY CONFIDENT

1231
00:57:23,180 --> 00:57:24,481
IF YOU HAVE CELLS SHOW THERE IS

1232
00:57:24,481 --> 00:57:25,949
A CELLULAR DEFECT IN THE

1233
00:57:25,949 --> 00:57:29,019
RESPONSE TO UV AND THAT CAN BE

1234
00:57:29,019 --> 00:57:34,558
CORRECTED BY THE GENE YOU

1235
00:57:34,558 --> 00:57:39,096
IDENTIFIED, CDNA AND ALTHOUGH IF

1236
00:57:39,096 --> 00:57:42,999
I'M CORRECT I THINK YOU ARE IN

1237
00:57:42,999 --> 00:57:44,468
MOROCCO AND YOU HAVE FACILITIES

1238
00:57:44,468 --> 00:57:46,203
THERE, SURE YOU CAN FIND

1239
00:57:46,203 --> 00:57:47,070
COLLABORATORS WHO WOULD BE

1240
00:57:47,070 --> 00:57:50,474
PLEASED TO DO THOSE KINDS OF

1241
00:57:50,474 --> 00:57:51,708
EXPERIMENTS. IF YOU ARE NOT THE

1242
00:57:51,708 --> 00:57:53,043
PERSON I THINK YOU ARE.

1243
00:57:53,043 --> 00:57:56,046
>> IT SAYS NO
OPPORTUNITIES YET.

1244
00:57:56,046 --> 00:58:06,223
>> SORRY.

1245
00:58:06,423 --> 00:58:09,993
>> I THINK WE DON'T SEE
ANY

1246
00:58:09,993 --> 00:58:11,328
ADDITIONAL QUESTIONS. WITH THE

1247
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LIMITATION OF TIME WE WILL

1248
00:58:12,562 --> 00:58:14,197
PROBABLY JUST WRAP UP HERE AND

1249
00:58:14,197 --> 00:58:15,899
PLEASE JOIN ME IN THANKING DR.

1250
00:58:15,899 --> 00:58:17,400
LEHMANN AGAIN FOR THE WONDERFUL

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00:58:17,400 --> 00:58:20,737
OVERVIEW OF THE XP. THANK YOU,

1252
00:58:20,737 --> 00:58:23,940
EVERYBODY FOR THE PARTICIPATION.

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00:58:23,940 --> 00:58:28,311
IN JANUARY WE WILL HAVE OUR

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00:58:28,311 --> 00:58:31,181
VIDEO CONFERENCE CONTINUE WITH

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00:58:31,181 --> 00:58:34,885
ANDREA NUSSENSWAG AND FELLOW TO

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00:58:34,885 --> 00:58:36,286
PRESENT RECENT FINDINGS. THANK

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00:58:36,286 --> 00:58:39,856
YOU. SEE YOU NEXT TIME.

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00:58:39,856 --> 00:58:40,390
>> THANK YOU.

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00:58:40,390 --> 00:58:43,326
>> THANK YOU.

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00:58:43,326 --> 00:58:44,394
>> THANKS, ALAN.

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00:58:44,394 --> 00:58:54,738
>> WONDERFUL TALK.