title: Origin, functional role, and clinical impact of Fanconi anemia FANCA mutations.
abstract: Fanconi anemia is characterized by congenital abnormalities, bone marrow failure, and cancer predisposition. To investigate the origin, functional role, and clinical impact of FANCA mutations, we determined a FANCA mutational spectrum with 130 pathogenic alleles. Some of these mutations were further characterized for their distribution in populations, mode of emergence, or functional consequences at cellular and clinical level. The world most frequent FANCA mutation is not the result of a mutational "hot-spot" but results from worldwide dissemination of an ancestral Indo-European mutation. We provide molecular evidence that total absence of FANCA in humans does not reduce embryonic viability, as the observed frequency of mutation carriers in the Gypsy population equals the expected by Hardy-Weinberg equilibrium. We also prove that long distance Alu-Alu recombination can cause Fanconi anemia by originating large interstitial deletions involving FANCA and 2 adjacent genes. Finally, we show that all missense mutations studied lead to an altered FANCA protein that is unable to relocate to the nucleus and activate the FA/BRCA pathway. This may explain the observed lack of correlation between type of FANCA mutation and cellular phenotype or clinical severity in terms of age of onset of hematologic disease or number of malformations.
authors.affiliation: Genome Instability and DNA Repair Group, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Campus de Bellaterra s/n, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Castella
authors.forename: Roser
authors.initials: R
authors.lastname: Pujol
authors.forename: Elsa
authors.initials: E
authors.lastname: Callén
authors.forename: Juan P
authors.initials: JP
authors.lastname: Trujillo
authors.forename: José A
authors.initials: JA
authors.lastname: Casado
authors.forename: Hans
authors.initials: H
authors.lastname: Gille
authors.forename: Francis P
authors.initials: FP
authors.lastname: Lach
authors.forename: Arleen D
authors.initials: AD
authors.lastname: Auerbach
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
authors.forename: Beatriz
authors.initials: B
authors.lastname: Porto
authors.forename: Teresa
authors.initials: T
authors.lastname: Ferro
authors.forename: Arturo
authors.initials: A
authors.lastname: Muñoz
authors.forename: Julián
authors.initials: J
authors.lastname: Sevilla
authors.forename: Luis
authors.initials: L
authors.lastname: Madero
authors.forename: Elena
authors.initials: E
authors.lastname: Cela
authors.forename: Cristina
authors.initials: C
authors.lastname: Beléndez
authors.forename: Cristina Díaz
authors.initials: CD
authors.lastname: de Heredia
authors.forename: Teresa
authors.initials: T
authors.lastname: Olivé
authors.forename: José Sánchez
authors.initials: JS
authors.lastname: de Toledo
authors.forename: Isabel
authors.initials: I
authors.lastname: Badell
authors.forename: Montserrat
authors.initials: M
authors.lastname: Torrent
authors.forename: Jesús
authors.initials: J
authors.lastname: Estella
authors.forename: Angeles
authors.initials: A
authors.lastname: Dasí
authors.forename: Antonia
authors.initials: A
authors.lastname: Rodríguez-Villa
authors.forename: Pedro
authors.initials: P
authors.lastname: Gómez
authors.forename: José
authors.initials: J
authors.lastname: Barbot
authors.forename: María
authors.initials: M
authors.lastname: Tapia
authors.forename: Antonio
authors.initials: A
authors.lastname: Molinés
authors.forename: Angela
authors.initials: A
authors.lastname: Figuera
authors.forename: Juan A
authors.initials: JA
authors.lastname: Bueren
authors.forename: Jordi
authors.initials: J
authors.lastname: Surrallés
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D001483:Base Sequence; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D005199:Fanconi Anemia / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D005787:Gene Frequency; D006801:Humans; D007223:Infant; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D010641:Phenotype; D013030:Spain / Q000453:epidemiology
chemical_list: C498471:FANCA protein, human; D052217:Fanconi Anemia Complementation Group A Protein