title: Rescue of progeria in trichothiodystrophy by homozygous lethal Xpd alleles.
abstract: Although compound heterozygosity, or the presence of two different mutant alleles of the same gene, is common in human recessive disease, its potential to impact disease outcome has not been well documented. This is most likely because of the inherent difficulty in distinguishing specific biallelic effects from differences in environment or genetic background. We addressed the potential of different recessive alleles to contribute to the enigmatic pleiotropy associated with XPD recessive disorders in compound heterozygous mouse models. Alterations in this essential helicase, with functions in both DNA repair and basal transcription, result in diverse pathologies ranging from elevated UV sensitivity and cancer predisposition to accelerated segmental progeria. We report a variety of biallelic effects on organismal phenotype attributable to combinations of recessive Xpd alleles, including the following: (i) the ability of homozygous lethal Xpd alleles to ameliorate a variety of disease symptoms when their essential basal transcription function is supplied by a different disease-causing allele, (ii) differential developmental and tissue-specific functions of distinct Xpd allele products, and (iii) interallelic complementation, a phenomenon rarely reported at clinically relevant loci in mammals. Our data suggest a re-evaluation of the contribution of "null" alleles to XPD disorders and highlight the potential of combinations of recessive alleles to affect both normal and pathological phenotypic plasticity in mammals.
authors.affiliation: Medical Genetics Center, Department of Cell Biology and Genetics, Center of Biomedical Genetics, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Jaan-Olle
authors.initials: JO
authors.lastname: Andressoo
authors.forename: Judith
authors.initials: J
authors.lastname: Jans
authors.forename: Jan
authors.initials: J
authors.lastname: de Wit
authors.forename: Frederic
authors.initials: F
authors.lastname: Coin
authors.forename: Deborah
authors.initials: D
authors.lastname: Hoogstraten
authors.forename: Marieke
authors.initials: M
authors.lastname: van de Ven
authors.forename: Wendy
authors.initials: W
authors.lastname: Toussaint
authors.forename: Jan
authors.initials: J
authors.lastname: Huijmans
authors.forename: H Bing
authors.initials: HB
authors.lastname: Thio
authors.forename: Wibeke J
authors.initials: WJ
authors.lastname: van Leeuwen
authors.forename: Jan
authors.initials: J
authors.lastname: de Boer
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Egly
authors.forename: Jan H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
authors.forename: James R
authors.initials: JR
authors.lastname: Mitchell
mesh_terms: D000483:Alleles; D000818:Animals; D004249:DNA Damage; D005804:Genes, Lethal; D005808:Genes, Recessive; D006130:Growth Disorders / Q000235:genetics* / Q000473:pathology; D006201:Hair Diseases / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007057:Ichthyosis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011371:Progeria / Q000235:genetics* / Q000378:metabolism; D051758:Transcription Factor TFIIH / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014466:Ultraviolet Rays; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*
chemical_list: D051758:Transcription Factor TFIIH; D051759:Xeroderma Pigmentosum Group D Protein; C497293:Ercc2 protein, mouse