title: Effects of compound heterozygosity at the Xpd locus on cancer and ageing in mouse models.
abstract: XPD is a helicase subunit of transcription factor IIH, an eleven-protein complex involved in a wide range of cellular activities including transcription and nucleotide excision DNA repair (NER). Mutations in NER genes including XPD can lead to a variety of overlapping syndromes with three general categories of symptoms in addition to sun (UV) sensitivity: severe skin cancer predisposition as in xeroderma pigmentosum (XP), segmental progeria as in trichothiodystrophy (TTD) and Cockayne syndrome (CS), and a combination of both as in XP/CS and XP/TTD. Genetic background and compound heterozygosity are two factors potentially complicating straightforward interpretations of genotype-phenotype relationship at the XPD locus. Previously we showed that the presence of two different mutant Xpd alleles in compound heterozygous mice could in principle contribute to disease heterogeneity through biallelic effects, including dominance of one mutant allele over another and interallelic complementation between mutant alleles, in a tissue-specific manner. Here we report on the interaction between different mutant alleles in compound heterozygous mice carrying one XP/CS-associated allele (Xpd(G602D)) and one TTD-associated allele (Xpd(R722W)) relative to homozygous controls in an isogenic background over a range of metabolic and UV-induced DNA damage-related phenotypes. We found complementation of metabolic phenotypes including body weight and insulin sensitivity, but none for any of the measured responses to UV irradiation. Instead, we found dominance of the partially functional TTD allele over the XPCS allele in most aspects of the response to UV irradiation including sunburn and skin cancer in vivo or cellular proliferation and DNA damage foci formation in vitro. These data support to a model of genotype-phenotype relationship at the XPD locus in which interactions between different recessive diseases alleles are a potent source of disease heterogeneity in compound heterozygous patients.
authors.affiliation: Medical Genetics Center, Department of Cell Biology and Genetics, Center of Biomedical Genetics, P.O. Box 1738, Erasmus MC, 3000DR Rotterdam, The Netherlands. m.vd.ven@nki.nl
authors.forename: Marieke
authors.initials: M
authors.lastname: van de Ven
authors.forename: Jaan-Olle
authors.initials: JO
authors.lastname: Andressoo
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
authors.forename: Jan H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.forename: James R
authors.initials: JR
authors.lastname: Mitchell
mesh_terms: D000375:Aging / Q000235:genetics*; D000483:Alleles; D000818:Animals; D001835:Body Weight / Q000235:genetics; D003057:Cockayne Syndrome / Q000235:genetics; D004249:DNA Damage; D004195:Disease Models, Animal; D005799:Genes, Dominant; D006579:Heterozygote; D007333:Insulin Resistance / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D012878:Skin Neoplasms / Q000235:genetics*; D054463:Trichothiodystrophy Syndromes / Q000235:genetics; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000235:genetics; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*
chemical_list: D051759:Xeroderma Pigmentosum Group D Protein; C497293:Ercc2 protein, mouse