Origin, functional role, and clinical impact of Fanconi anemia FANCA mutations.

Autores de IIS La Fe

• Ignacio Benítez Sánchez

  Autor

• Sacramento Rodriguez Ferron

  Autor

• Alberto Muñoz Cano

  Autor

• Juan Sevilla Gasco

  Autor

• Carlos Estella Sagrado

  Autor

• María De Los Ángeles Dasi Carpio

  Autor

• Adriana Rodríguez Vidal

  Autor

• Pau Gomez Cabezas

  Autor

Participantes ajenos a IIS La Fe

• Castella M
• Pujol R
• Callén E
• Trujillo JP
• Casado JA
• Gille H
• Lach FP
• Auerbach AD
• Schindler D
• Porto B
• Madero L
• Cela E
• Beléndez C
• de Heredia CD
• Olivé T
• de Toledo JS
• Badell I
• Torrent M
• Barbot J
• Tapia M
• Molinés A
• Figuera A
• Bueren JA
• Surrallés J

Grupos

• Hemostasia, Trombosis, Arteriosclerosis y Biología vascular

  

  Investigador Principal

  Pilar Medina Badenes

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.