title: Both XPD alleles contribute to the phenotype of compound heterozygote xeroderma pigmentosum patients.
abstract: Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH result in the rare recessive genetic disorder xeroderma pigmentosum (XP). Many XP patients are compound heterozygotes with a "causative" XPD point mutation R683W and different second mutant alleles, considered "null alleles." However, there is marked clinical heterogeneity (including presence or absence of skin cancers or neurological degeneration) in these XPD/R683W patients, thus suggesting a contribution of the second allele. Here, we report XP patients carrying XPD/R683W and a second XPD allele either XPD/Q452X, /I455del, or /199insPP. We performed a systematic study of the effect of these XPD mutations on several enzymatic functions of TFIIH and found that each mutation exhibited unique biochemical properties. Although all the mutations inhibited the nucleotide excision repair (NER) by disturbing the XPD helicase function, each of them disrupted specific molecular steps during transcription: XPD/Q452X hindered the transactivation process, XPD/I455del disturbed RNA polymerase II phosphorylation, and XPD/199insPP inhibited kinase activity of the cdk7 subunit of TFIIH. The broad range and severity of clinical features in XP patients arise from a broad set of deficiencies in NER and transcription that result from the combination of mutations found on both XPD alleles.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 10142, 67404 Illkirch Cedex, C.U. Strasbourg, France.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ueda
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Compe
authors.forename: Philippe
authors.initials: P
authors.lastname: Catez
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Kraemer
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Egly
mesh_terms: D000328:Adult; D000483:Alleles; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006579:Heterozygote; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000032:analysis; D008297:Male; D010641:Phenotype; D017354:Point Mutation; D018411:Spodoptera; D051758:Transcription Factor TFIIH / Q000032:analysis; D014158:Transcription, Genetic; D014983:Xeroderma Pigmentosum / Q000235:genetics*; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*
chemical_list: C489676:KLF9 protein, human; D051741:Kruppel-Like Transcription Factors; D051758:Transcription Factor TFIIH; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human