Hypomorphic mutations in the gene encoding a key Fanconi anemia protein, FANCD2, sustain a significant group of FA-D2 patients with severe phenotype

Reinhard Kalb, Kornelia Neveling, Holger Hoehn, Hildegard Schneider, Yvonne Linka, Sat Dev Batish, Curtis Hunt, Marianne Berwick, Elsa Callén, Jordi Surrallés, José A. Casado, Juan Bueren, Ángeles Dasí, Jean Soulier, Eliane Gluckman, C. Michel Zwaan, Rosalina Van Spaendonk, Gerard Pals, Johan P. De Winter, Hans JoenjeMarkus Grompe, Arleen D. Auerbach, Helmut Hanenberg, Detlev Schindler

Research output: Contribution to journalArticle

84 Scopus citations

Abstract

FANCD2 is an evolutionarily conserved Fanconi anemia (FA) gene that plays a key role in DNA double-strand-type damage responses. Using complementation assays and immunoblotting, a consortium of American and European groups assigned 29 patients with FA from 23 families and 4 additional unrelated patients to complementation group FA-D2. This amounts to 3%-6% of FA-affected patients registered in various data sets. Malformations are frequent in FA-D2 patients, and hematological manifestations appear earlier and progress more rapidly when compared with all other patients combined (FA-non-D2) in the International Fanconi Anemia Registry. 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 allelic haplotypes. There were no biallelic null mutations; residual FANCD2 protein of both isotypes was observed in all available patient cell lines. These analyses suggest that, unlike the knockout mouse model, total absence of FANCD2 does not exist in FA-D2 patients, because of constraints on viable combinations of FANCD2 mutations. Although hypomorphic mutations arie involved, clinically, these patients have a relatively severe form of FA.

Original languageEnglish (US)
Pages (from-to)895-910
Number of pages16
JournalAmerican Journal of Human Genetics
Volume80
Issue number5
DOIs
StatePublished - May 2007

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Kalb, R., Neveling, K., Hoehn, H., Schneider, H., Linka, Y., Batish, S. D., Hunt, C., Berwick, M., Callén, E., Surrallés, J., Casado, J. A., Bueren, J., Dasí, Á., Soulier, J., Gluckman, E., Zwaan, C. M., Van Spaendonk, R., Pals, G., De Winter, J. P., ... Schindler, D. (2007). Hypomorphic mutations in the gene encoding a key Fanconi anemia protein, FANCD2, sustain a significant group of FA-D2 patients with severe phenotype. American Journal of Human Genetics, 80(5), 895-910. https://doi.org/10.1086/517616