Mutations in the XPD gene in xeroderma pigmentosum group D cell strains: confirmation of genotype-phenotype correlation.
Xeroderma pigmentosum (XP) is a sun-sensitive and cancer-prone genetic disorder consisting of seven genetically distinct complementation groups (groups A-G). XP group D (XP-D) is a heterogeneous group. Mutations in the XPD gene (XPD) can exhibit three distinct clinical phenotypes: XP, trichothiodystrophy (TTD), or XP combined with Cockayne syndrome. XPD protein is required for both nucleotide excision repair (NER) and basal transcription. Therefore, different mutations in XPD may affect NER and transcription activities to various degrees and result in such diverse phenotypes. In this study, we identified six causative mutations, two of which have not been described, in five XP-D cell strains tested. The cell strains were all compound heterozygotes with different mutations. In all cell strains, one allele was thought to be functionally null and the other was a less severe allele with R683W, R683Q, and R666W substitutions. The second allele in each strain was specific to the XP phenotype. The findings are consistent with the hypothesis that the site of mutation of the XPD gene determines the clinical phenotype, XP or TTD.
Department of Pediatrics, Niigata University School of Medicine, Niigata, Japan. takekoba@med.niigata-u.ac.jp
Takehiro
T
Kobayashi
Makoto
M
Uchiyama
Shuhei
S
Fukuro
Kiyoji
K
Tanaka
D000328:Adult; D000368:Aged; D001483:Base Sequence; D002478:Cells, Cultured; D002648:Child; D004265:DNA Helicases; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D017384:Sequence Deletion; D014157:Transcription Factors; D014983:Xeroderma Pigmentosum / Q000235:genetics* / Q000473:pathology; D051759:Xeroderma Pigmentosum Group D Protein
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D011506:Proteins; D014157:Transcription Factors; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human