期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 92, 期 5, 页码 800-806出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2013.04.002
关键词
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资金
- European Program 7FWP, Health (PERSIST) [222878]
- Spanish Ministry of Science and Innovation [Refs110-90.1, SAP 2009-07164]
- Fundacion Botin
- National Institutes of Health [GM080454, CA092584]
- CCA/V-ICI Amsterdam
- Deutsche Fanconi-Anaemie-Hilfe
- Aktionskreis Fanconi-Anaemie
- Schroeder-Kurth Fund
- Generalitat de Catalunya [SGR0489-2009]
- ICREA-Academia award
- Spanish Ministry of Science and Innovation (Centre for Biomedical Network Research on Rare Diseases [CIBERER]) [CB06/07/0023, SAF2009-11936, SAF2012-31881]
- European Regional Development FEDER Funds
- [Programa RETICS-RD06/0010/0015 ISCIII]
Fanconi anemia (FA) is a rare genomic instability disorder characterized by progressive bone marrow failure and predisposition to cancer. FA-associated gene products are involved in the repair of DNA interstrand crosslinks (ICLs). Fifteen FA-associated genes have been identified, but the genetic basis in some individuals still remains unresolved. Here, we used whole-exome and Sanger sequencing on DNA of unclassified FA individuals and discovered biallelic germline mutations in ERCC4 (XPF), a structure-specific nuclease-encoding gene previously connected to xeroderma pigmentosum and segmental XFE progeroid syndrome. Genetic reversion and wild-type ERCC4 cDNA complemented the phenotype of the FA cell lines, providing genetic evidence that mutations in ERCC4 cause this FA subtype. Further biochemical and functional analysis demonstrated that the identified FA-causing ERCC4 mutations strongly disrupt the function of XPF in DNA ICL repair without severely compromising nucleotide excision repair. Our data show that depending on the type of ERCC4 mutation and the resulting balance between both DNA repair activities, individuals present with one of the three clinically distinct disorders, highlighting the multifunctional nature of the XPF endonuclease in genome stability and human disease.
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