Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia
Bogliolo, Massimo (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Schuster, Beatrice (University of Würzburg. Department of Human Genetics (Würzburg, Alemanya))
Stoepker, Chantal (Vrije Universiteit Medical Center. Department of Clinical Genetics and Human Genetics)
Derkunt, Burak (State University of New York at Stony Brook. Department of Pharmacological Sciences and Chemistry)
Su, Yan (State University of New York at Stony Brook. Department of Pharmacological Sciences and Chemistry)
Raams, Anja (Erasmus MC Universitair Medisch Centrum Rotterdam)
Trujillo Quintero, Juan Pablo (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Minguillón Pedreño, Jordi (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Ramírez de Haro, Ma. José (María José) (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Pujol i Calvet, M. Roser (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Casado, José A. (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Baños, Rocío (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Río, Paula (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Knies, Kerstin (University of Würzburg. Department of Human Genetics (Würzburg, Alemanya)))
Zúñiga, Sheila (Sistemas Genómicos. Departamento de Bioinformática)
Benitez, Javier (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Bueren, Juan (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Jaspers, Nicolaas G. J. (Erasmus MC Universitair Medisch Centrum Rotterdam)
Schärer, Orlando D. (State University of New York at Stony Brook. Department of Pharmacological Sciences and Chemistry)
Winter, Johan P. de (Vrije Universiteit Medical Center. Department of Clinical Genetics and Human Genetics)
Schindler, Detlev (University of Würzburg. Department of Human Genetics (Würzburg, Alemanya))
Surrallés i Calonge, Jordi (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)

Fecha:	2013
Resumen:	BFanconi 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.
Derechos:	Tots els drets reservats.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió acceptada per publicar
Materia:	Fanconi anemia ; DNA
Publicado en:	American journal of human genetics, Vol. 92 (May 2013) , p. 800-806, ISSN 0002-9297

DOI: 10.1016/j.ajhg.2013.04.002
PMID: 23623386

Post-print 29 p, 2.6 MB

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