title: A novel XPD mutation in a compound heterozygote; the mutation in the second allele is present in three homozygous patients with mild sun sensitivity.
abstract: The XPD protein plays a pivotal role in basal transcription and in nucleotide excision repair (NER) as one of the ten known components of the transcription factor TFIIH. Mutations in XPD can result in the DNA repair-deficient diseases xeroderma pigmentosum (XP), trichothiodystrophy (TTD), cerebro-oculo-facial-skeletal syndrome, and in combined phenotypes such as XP/Cockayne syndrome and XP/TTD. We describe here an 18-year-old individual with mild sun sensitivity, no neurological abnormalities and no tumors, who carries a p.R683Q mutation in one allele, and the novel p.R616Q mutation in the other allele of the XPD gene. We also describe four patients from one family, homozygous for the identical p.R683Q mutation in XPD, who exhibit mild skin pigmentation and loss of tendon reflexes. Three homozygous patients presented with late-onset skin tumors, and two with features of premature aging and moderate cognitive decline. Cells from the compound heterozygous individual and from one of the patients homozygous for p.R683Q exhibited similar responses to UV irradiation: reduced viability and defective overall removal of UV-induced cyclobutane pyrimidine dimers, implying deficient global genomic NER. Cells from the compound heterozygous subject also failed to recover RNA synthesis after UV, indicating defective transcription-coupled NER. Mutations affecting codon 616 in XPD generally result in functionally null proteins; we hypothesize that the phenotype of the heterozygous patient results solely from expression of the p.R683Q allele. This study illustrates the importance of detailed follow up with sun sensitive individuals, to ensure appropriate prophylaxis and to understand the mechanistic basis of the implicated hereditary disease.
authors: Institute of Human Genetics, Western Galilee Hospital, Naharia, Israel. falikmd.genetics@gmail.com
authors: Tzipora C
authors: TC
authors: Falik-Zaccai
authors: Reut
authors: R
authors: Erel-Segal
authors: Liran
authors: L
authors: Horev
authors: Ora
authors: O
authors: Bitterman-Deutsch
authors: Sivan
authors: S
authors: Koka
authors: Sara
authors: S
authors: Chaim
authors: Zohar
authors: Z
authors: Keren
authors: Limor
authors: L
authors: Kalfon
authors: Bella
authors: B
authors: Gross
authors: Zvi
authors: Z
authors: Segal
authors: Shlomi
authors: S
authors: Orgal
authors: Yishay
authors: Y
authors: Shoval
authors: Hanoch
authors: H
authors: Slor
authors: Graciela
authors: G
authors: Spivak
authors: Philip C
authors: PC
authors: Hanawalt
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005816:Genetic Complementation Test; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D010787:Photosensitivity Disorders / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013472:Sunlight; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human