Clinical, Cellular, and Molecular Features of an Israeli Xeroderma Pigmentosum Family with a Frameshift Mutation in the XPC Gene: Sun Protection Prolongs Life

Abstract

An Ashkenazi Jewish Israeli family with two children affected with severe xeroderma pigmentosum was investigated. A son, XP12TA, developed skin cancer at 2 y and died at 10 y. A daughter, XP25TA, now 24 y old, was sun protected and began developing skin cancers at 10 y. Their cultured skin fibroblasts showed reductions in post-ultraviolet survival (11% of normal), unscheduled DNA synthesis (10% of normal), global genome DNA repair (15% of normal), and plasmid host cell reactivation (5% of normal). Transcription-coupled DNA repair was normal, however. Northern blot analysis revealed greatly reduced xeroderma pigmentosum complementation group C mRNA. A plasmid host cell reactivation assay assigned the cells to xeroderma pigmentosum complementation group C. Cells from both parents and an unaffected child exhibited normal post-ultraviolet-C survival and normal DNA repair. Sequencing the xeroderma pigmentosum complementation group C cDNA of XP12TA and XP25TA revealed a homozygous deletion of two bases (del AT 669-670) in exon 5 with a new termination site 10 codons downstream that is expected to encode a truncated xeroderma pigmentosum complementation group C protein. Sequence analysis of the xeroderma pigmentosum complementation group C cDNA in cells from the parents found identical heterozygous mutations: one allele carries both the exon 5 frameshift and an exon 15 polymorphism and the other allele carries neither alteration. Cells from the unaffected brother had two normal xeroderma pigmentosum complementation group C alleles. This frameshift mutation in the xeroderma pigmentosum complementation group C gene led to reduced DNA repair with multiple skin cancers and early death. Sun protection delayed the onset of skin cancer and prolonged life in a sibling with the same mutation.

High frequency of the V548A fs X572 XPC mutation in Tunisia: implication for molecular diagnosis

“…The severity of this disease among Tunisian patients is similar to that described previously in North African, Italian, Turkish and Ashkenazi-Jewish Israeli patients. [16][17][18] The V548A fs X572 mutation affects the C-ter of the XPC protein residues 492-940. These residues had critical interactions with DNA, RAD23B, CETN2 and TFIIH.…”

Clinical utility gene card for: Xeroderma pigmentosum

“…Here, a phenotype correlation emerges indicating that XPC mutations only result in a classical XP phenotype. [5][6][7][8] XPD/ERCC2: 48 known disease-causing mutations from 32 XP patients (36 trichothiodystrophy patients are excluded). Mutations: 43 (90%) base exchanges and 5 (10%) deletions.…”

Cockayne syndrome type II in a Druze isolate in Northern Israel in association with an insertion mutation in ERCC6

“…This assay, which is also Known as Recovery of RNA Synthesis (RRS), specifically measures DNA repair in actively transcribed genes, was performed as described previously [Slor et al, 2000] with minor modifications (Fibroblast cultures were UV irradiated with 8 J/m 2 ).…”

“…CFA was performed as described previously [Slor et al, 2000] with minor modifications (Fibroblast cultures were UV irradiated with doses of 0-10 J/m 2 ).…”

“…Box 21, Nahariya 22100, Israel. E-mail: tzipora.falik@naharia.health.gov.il DOI 10.1002/ajmg.a.32309 occurrence of rare, autosomal recessive, devastating disorders such as xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD) [Nance and Berry, 1992;Slor et al, 2000;de Bohr and Hoeijmarkers, 2000;Christmann et al, 2003;Lehmann, 2003;Saxowsky and Doetsch, 2005]. CS is characterized by severe growth retardation, progressive neurological dysfunction and clinical symptoms of accelerated aging.…”