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PMID:17020410

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Citation

Andressoo, JO, Jans, J, de Wit, J, Coin, F, Hoogstraten, D, van de Ven, M, Toussaint, W, Huijmans, J, Thio, HB, van Leeuwen, WJ, de Boer, J, Egly, JM, Hoeijmakers, JH, van der Horst, GT and Mitchell, JR (2006) Rescue of progeria in trichothiodystrophy by homozygous lethal Xpd alleles. PLoS Biol. 4:e322

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.

Links

PubMed PMC1584416 Online version:10.1371/journal.pbio.0040322

Keywords

Alleles; Animals; DNA Damage; Genes, Lethal; Genes, Recessive; Growth Disorders/genetics; Growth Disorders/pathology; Hair Diseases/genetics; Homozygote; Humans; Ichthyosis/genetics; Mice; Mice, Inbred C57BL; Phenotype; Progeria/genetics; Progeria/metabolism; Transcription Factor TFIIH/genetics; Transcription Factor TFIIH/metabolism; Transcription, Genetic; Ultraviolet Rays; Xeroderma Pigmentosum Group D Protein/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:ERCC2

acts_upstream_of_or_within

GO:0022405: hair cycle process

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2183949

P

Seeded From UniProt

complete

MOUSE:ERCC2

acts_upstream_of_or_within

GO:0021510: spinal cord development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2183949

P

  • results_in_development_of:(EMAPA:17577)

Seeded From UniProt

complete

MOUSE:ERCC2

acts_upstream_of_or_within

GO:0001701: in utero embryonic development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3693615
MGI:MGI:3696121

P

Seeded From UniProt

complete

MOUSE:ERCC2

acts_upstream_of_or_within

GO:0007568: aging

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2183949

P

Seeded From UniProt

complete

MOUSE:ERCC2

acts_upstream_of_or_within

GO:0030282: bone mineralization

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2183949

P

Seeded From UniProt

complete

MOUSE:ERCC2

acts_upstream_of_or_within

GO:0009791: post-embryonic development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2183949

P

Seeded From UniProt

complete

MOUSE:ERCC2

acts_upstream_of_or_within

GO:0009411: response to UV

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2183949

P

Seeded From UniProt

complete

MOUSE:ERCC2

acts_upstream_of_or_within

GO:0043588: skin development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2183949

P

  • results_in_development_of:(EMAPA:32787)|results_in_development_of:(EMAPA:32786)

Seeded From UniProt

complete

MOUSE:ERCC2

acts_upstream_of_or_within

GO:0043249: erythrocyte maturation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2183949

P

Seeded From UniProt

complete

MOUSE:ERCC2

acts_upstream_of_or_within

GO:0035315: hair cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2183949

P

  • occurs_in:(EMAPA:18769)

Seeded From UniProt

complete

MOUSE:ERCC2

acts_upstream_of_or_within

GO:0035264: multicellular organism growth

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2183949

P

Seeded From UniProt

complete

See also

References

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