Rescue of progeria in trichothiodystrophy by homozygous lethal Xpd alleles

Jaan-Olle Andressoo, Judith Jans, Jan de Wit, Frederic Coin, Deborah Hoogstraten, Marieke van de Ven, Wendy Toussaint, Jan Huijmans, H. Bing Thio, Wibeke J. van Leeuwen, Jan de Boer, Jean-Marc Egly, Jan H. J. Hoeijmakers, Gijsbertus T. J. van der Horst, James R. Mitchell*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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 languageEnglish
Article number322
Pages (from-to)1821-1830
Number of pages10
JournalPLoS Biology
Volume4
Issue number10
DOIs
Publication statusPublished - Oct 2006

Keywords

  • REPAIR SYNDROME TRICHOTHIODYSTROPHY
  • XERODERMA-PIGMENTOSUM
  • DNA-REPAIR
  • BASAL TRANSCRIPTION
  • COCKAYNE-SYNDROME
  • INTERALLELIC COMPLEMENTATION
  • FACTOR TFIIH
  • MOUSE MODEL
  • MUTATIONS
  • DEFECT

Fingerprint

Dive into the research topics of 'Rescue of progeria in trichothiodystrophy by homozygous lethal Xpd alleles'. Together they form a unique fingerprint.

Cite this