Hypomorphic Mutations in the Central Fanconi Anemia Gene FANCD2 Sustain a Significant Group of FA-D2 Patients with Severe Phenotype. Running title : FA-D2 phenotype and FANCD2 mutations

Premi a l'excel·lència investigadora. Àmbit de les Ciències de la Salut. 2008FANCD2 is an evolutionarily conserved Fanconi anemia (FA) gene that plays a central role in DNA double-strand type damage responses. Using complementation assays and immunoblotting, a consortium of American and European groups assigned 29 FA patients from 23 families and 4 additional unrelated patients to complementation group FA-D2. This amounts to 3 to 6% of FA patients registered in various datasets. Malformations are frequent in FA-D2 patients and hematological manifestations appear earlier and progress more rapidly when compared to patients from all other FA groups combined, as represented by the International Fanconi Anemia Registry, IFAR. FANCD2 is flanked by two pseudogenes. Mutation analysis revealed the expected total of 66 mutated alleles, 34 of which result in aberrant splicing patterns. Many mutations are recurrent and have ethnic associations and shared alleles. There were no biallelic null mutations so that residual FANCD2 protein of both isotypes was observed in all patients' cell lines available. These analyses suggest that unlike in a knock-out mouse model, total absence of FANCD2 is not existing in FA-D2 patients due to constraints on viable combinations of FANCD2 mutations. Although hypomorphic mutations are involved, the result generally is a relatively severe form of FA