Origin, functional role, and clinical impact of fanconi anemia fanca mutations

Maria Castella, Roser Pujol, Elsa Callén, Juan P. Trujillo, José A. Casado, Hans Gille, Francis P. Lach, Arleen D. Auerbach, Detlev Schindler, Javier Benítez, Beatriz Porto, Teresa Ferro, Munoz Arturo, Julián Sevilla, Luis Madero, Elena Cela, Cristina Beléndez, Cristina Díaz De Heredia, Teresa Olivé, José Sánchez De ToledoIsabel Badell, Montserrat Torrent, Jesús Estella, Ángeles Dasí, Antonia Rodríguez-Villa, Pedro Gémez, José Barbot, María Tapia, Antonio Molinés, Ángela Figuera, Juan A. Bueren, Jordi Surrallés

Research output: Contribution to journalArticleResearchpeer-review

80 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)3759-3769
JournalBlood
Volume117
DOIs
Publication statusPublished - 7 Apr 2011

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