Xeroderma pigmentosum-variant patients from America, Europe, and Asia.
Xeroderma pigmentosum-variant (XP-V) patients have sun sensitivity and increased skin cancer risk. Their cells have normal nucleotide excision repair, but have defects in the POLH gene encoding an error-prone polymerase, DNA polymerase eta (pol eta). To survey the molecular basis of XP-V worldwide, we measured pol eta protein in skin fibroblasts from putative XP-V patients (aged 8-66 years) from 10 families in North America, Turkey, Israel, Germany, and Korea. Pol eta was undetectable in cells from patients in eight families, whereas two showed faint bands. DNA sequencing identified 10 different POLH mutations. There were two splicing, one nonsense, five frameshift (3 deletion and 2 insertion), and two missense mutations. Nine of these mutations involved the catalytic domain. Although affected siblings had similar clinical features, the relation between the clinical features and the mutations was not clear. POLH mRNA levels were normal or reduced by 50% in three cell strains with undetectable levels of pol eta protein, indicating that nonsense-mediated message decay was limited. We found a wide spectrum of mutations in the POLH gene among XP-V patients in different countries, suggesting that many of these mutations arose independently.
Inui
Hiroki
H
DNA Repair Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-4258, USA.
Oh
Kyu-Seon
KS
Nadem
Carine
C
Ueda
Takahiro
T
Khan
Sikandar G
SG
Metin
Ahmet
A
Gozukara
Engin
E
Emmert
Steffen
S
Slor
Hanoch
H
Busch
David B
DB
Baker
Carl C
CC
DiGiovanna
John J
JJ
Tamura
Deborah
D
Seitz
Cornelia S
CS
Gratchev
Alexei
A
Wu
Wen Hao
WH
Chung
Kee Yang
KY
Chung
Hye Jin
HJ
Azizi
Esther
E
Woodgate
Roger
R
Schneider
Thomas D
TD
Kraemer
Kenneth H
KH
D000293:Adolescent; D000328:Adult; D000368:Aged; D001208:Asia; D002648:Child; D018389:Codon, Nonsense / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics* / Q000378:metabolism; D005060:Europe; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D016368:Frameshift Mutation / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009656:North America; D010375:Pedigree; D012333:RNA, Messenger / Q000378:metabolism; D014983:Xeroderma Pigmentosum / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D000099270:Y-Family DNA Polymerases
D018389:Codon, Nonsense; D004259:DNA-Directed DNA Polymerase; D012333:RNA, Messenger; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases