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.
Original language | English |
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Article number | 322 |
Pages (from-to) | 1821-1830 |
Number of pages | 10 |
Journal | PLoS Biology |
Volume | 4 |
Issue number | 10 |
DOIs | |
Publication status | Published - Oct 2006 |
Keywords
- REPAIR SYNDROME TRICHOTHIODYSTROPHY
- XERODERMA-PIGMENTOSUM
- DNA-REPAIR
- BASAL TRANSCRIPTION
- COCKAYNE-SYNDROME
- INTERALLELIC COMPLEMENTATION
- FACTOR TFIIH
- MOUSE MODEL
- MUTATIONS
- DEFECT