title: Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia.
abstract: 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.
authors.affiliation: Genome Instability and DNA Repair Group, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bogliolo
authors.forename: Beatrice
authors.initials: B
authors.lastname: Schuster
authors.forename: Chantal
authors.initials: C
authors.lastname: Stoepker
authors.forename: Burak
authors.initials: B
authors.lastname: Derkunt
authors.forename: Yan
authors.initials: Y
authors.lastname: Su
authors.forename: Anja
authors.initials: A
authors.lastname: Raams
authors.forename: Juan P
authors.initials: JP
authors.lastname: Trujillo
authors.forename: Jordi
authors.initials: J
authors.lastname: Minguillón
authors.forename: María J
authors.initials: MJ
authors.lastname: Ramírez
authors.forename: Roser
authors.initials: R
authors.lastname: Pujol
authors.forename: José A
authors.initials: JA
authors.lastname: Casado
authors.forename: Rocío
authors.initials: R
authors.lastname: Baños
authors.forename: Paula
authors.initials: P
authors.lastname: Rio
authors.forename: Kerstin
authors.initials: K
authors.lastname: Knies
authors.forename: Sheila
authors.initials: S
authors.lastname: Zúñiga
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
authors.forename: Juan A
authors.initials: JA
authors.lastname: Bueren
authors.forename: Nicolaas G J
authors.initials: NG
authors.lastname: Jaspers
authors.forename: Orlando D
authors.initials: OD
authors.lastname: Schärer
authors.forename: Johan P
authors.initials: JP
authors.lastname: de Winter
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
authors.forename: Jordi
authors.initials: J
authors.lastname: Surrallés
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics*; D003851:Deoxyribonucleases / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005199:Fanconi Anemia / Q000235:genetics* / Q000473:pathology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008969:Molecular Sequence Data; D010641:Phenotype; D017422:Sequence Analysis, DNA; D014466:Ultraviolet Rays
chemical_list: D004268:DNA-Binding Proteins; C095888:xeroderma pigmentosum group F protein; D003851:Deoxyribonucleases