title: Two individuals with features of both xeroderma pigmentosum and trichothiodystrophy highlight the complexity of the clinical outcomes of mutations in the XPD gene.
abstract: The xeroderma pigmentosum group D (XPD) protein is a subunit of transcription factor TFIIH with DNA helicase activity. TFIIH has two functions, in basal transcription and nucleotide excision repair. Mutations in XPD that affect DNA repair but not transcription result in the skin cancer-prone disorder, xeroderma pigmentosum (XP). If transcription is also affected, the result is the multi-system disorder trichothiodystrophy (TTD), in which there is no skin cancer predisposition, or in rare cases, XP combined with Cockayne syndrome. Up till now there have been no reports of combined clinical features of XP and TTD. We have now identified two patients with some features of both these disorders. One of these, XP189MA, a 3-year-old girl with sun sensitivity, mental and physical developmental delay, has XPD mutations not previously reported, and barely detectable levels of nucleotide excision repair. The other, XP38BR, a 28-year-old woman with sun sensitivity, pigmentation changes and skin cancers typical of XP, has a mutation that has been identified previously, but only in TTD patients with no features of XP. The level of repair of UV damage in XP38BR is substantially higher than that in other patients with the same mutation. With both patients, polarized light microscopy revealed a 'tiger-tail' appearance of the hair, and amino acid analysis of the hair shafts show levels of sulfur-containing proteins intermediate between those of normal and TTD individuals. Our findings highlight the complexities of genotype-phenotype relationships in the XPD gene.
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RR, UK.
authors.forename: B C
authors.initials: BC
authors.lastname: Broughton
authors.forename: M
authors.initials: M
authors.lastname: Berneburg
authors.forename: H
authors.initials: H
authors.lastname: Fawcett
authors.forename: E M
authors.initials: EM
authors.lastname: Taylor
authors.forename: C F
authors.initials: CF
authors.lastname: Arlett
authors.forename: T
authors.initials: T
authors.lastname: Nardo
authors.forename: M
authors.initials: M
authors.lastname: Stefanini
authors.forename: E
authors.initials: E
authors.lastname: Menefee
authors.forename: V H
authors.initials: VH
authors.lastname: Price
authors.forename: S
authors.initials: S
authors.lastname: Queille
authors.forename: A
authors.initials: A
authors.lastname: Sarasin
authors.forename: E
authors.initials: E
authors.lastname: Bohnert
authors.forename: J
authors.initials: J
authors.lastname: Krutmann
authors.forename: R
authors.initials: R
authors.lastname: Davidson
authors.forename: K H
authors.initials: KH
authors.lastname: Kraemer
authors.forename: A R
authors.initials: AR
authors.lastname: Lehmann
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000528:radiation effects; D001483:Base Sequence; D002470:Cell Survival / Q000528:radiation effects; D002478:Cells, Cultured; D002675:Child, Preschool; D004265:DNA Helicases; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D004268:DNA-Binding Proteins; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006201:Hair Diseases / Q000235:genetics* / Q000473:pathology; D006801:Humans; D009154:Mutation; D010787:Photosensitivity Disorders / Q000235:genetics / Q000473:pathology; D011506:Proteins / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000235:genetics* / Q000473:pathology; D051759:Xeroderma Pigmentosum Group D Protein
chemical_list: 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