title: Molecular genetic analysis of 16 XP-C patients from Germany: environmental factors predominately contribute to phenotype variations.
abstract: Patients belonging to xeroderma pigmentosum (XP) complementation group C comprise one-third of all XP patients. Only four major reports compiled larger groups of XP-C patients from southern Europe (12 pts), North America (16 pts) and Africa (14 and 56 pts) as well as their genetic background (46 XPC mutations). We identified 16 XP-C patients from Germany. Interestingly, only five patients exhibited severe sun sensitivity. The mean age of XP diagnosis was 9.4 years, and the median age of the first skin cancer was 7 years. Neurological symptoms were absent in all but two patients. Primary fibroblasts from all 16 patients showed reduced post-UV cell survival (mean: 50% vs 93% in normal cells) and reduced reactivation of an UV-treated luciferase reporter gene (mean: 6.4% vs 30.7% in normal cells). XPC mRNA expression was also greatly reduced compared with normal cells (mean: 14.3%; range 8.3-25.7%) except in XP47MA (274.1%). All patients carried homozygous XPC mutations. Four mutations have been described previously: c.1747_1748delTG (found in 4/16), c.567 C>T (4/16), c.1839 C>T (1/16) and a complex insertion/deletion mutation in exon 9 (1/16). The novel frameshift mutations c.446_447delAG (2/16), c.1525insA (1/16) and c.2271delC (1/16) lead to truncated XPC proteins as does the novel nonsense mutation c.843C>T (1/16). XP47MA carries an interesting mutation (c.2538_2540delATC; p.Ile812del) resulting in an in-frame single amino acid deletion. This mutation results in a classical XP phenotype, a non-functional XPC protein, but elevated XPC mRNA expression. Our study indicates that extrinsic factors may contribute to XP-C symptom severity due to nonsense-mediated message decay.
authors.affiliation: Department of Dermatology, Venerology and Allergology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Schäfer
authors.forename: Lars
authors.initials: L
authors.lastname: Hofmann
authors.forename: Alexei
authors.initials: A
authors.lastname: Gratchev
authors.forename: Petra
authors.initials: P
authors.lastname: Laspe
authors.forename: Steffen
authors.initials: S
authors.lastname: Schubert
authors.forename: Anke
authors.initials: A
authors.lastname: Schürer
authors.forename: Andreas
authors.initials: A
authors.lastname: Ohlenbusch
authors.forename: Mladen
authors.initials: M
authors.lastname: Tzvetkov
authors.forename: Christian
authors.initials: C
authors.lastname: Hallermann
authors.forename: Jörg
authors.initials: J
authors.lastname: Reichrath
authors.forename: Michael P
authors.initials: MP
authors.lastname: Schön
authors.forename: Steffen
authors.initials: S
authors.lastname: Emmert
mesh_terms: D000293:Adolescent; D000328:Adult; D002470:Cell Survival / Q000528:radiation effects; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004777:Environment; D005260:Female; D005347:Fibroblasts / Q000528:radiation effects; D016368:Frameshift Mutation; D005858:Germany; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D009422:Nervous System Diseases / Q000150:complications; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics*; D013471:Sunburn / Q000209:etiology / Q000517:prevention & control; D013472:Sunlight / Q000009:adverse effects; D014983:Xeroderma Pigmentosum / Q000150:complications / Q000235:genetics*; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C086984:XPC protein, human