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
Kalba, Reinhard (University of Wurzburg. Department of Human Genetics)
Neveling, Kornelia (University of Wurzburg. Department of Human Genetics)
Hoehn, Holger (University of Wurzburg. Department of Human Genetics)
Schneider, Hildegard (University of Dusseldorf. Department of Pediatric Oncology, Hematology and Immunology)
Linka, Yvonne (University of Dusseldorf. Department of Pediatric Oncology, Hematology and Immunology)
Batishb, Sat Dev (The Rockefeller University. Laboratory of Human Genetics and Hematology)
Hunt, Curtis (University of New Mexico. Division of Epidemiology)
Berwick, Marianne (University of New Mexico. Division of Epidemiology)
Callén Moréu, Elsa (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Surrallés i Calonge, Jordi (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Casado, José A. (CIEMAT. Hematopoietic Gene Therapy Program)
Bueren, Juan (CIEMAT. Hematopoietic Gene Therapy Program)
Dasí, Ángeles (Hospital Universitari i Politècnic La Fe (València))
Soulier, Jean (Hopital Saint-Louis (Paris). Institut Universitaire d'Hematologie)
Gluckman, Eliane (Hopital Saint-Louis (Paris). Institut Universitaire d'Hematologie)
Zwaan, C. Michel (Erasmus MC Sophia Children's Hospital (Rotterdam). Department of Pediatric Hematology/Oncology)
Van Spaendonk, Rosalina (Vrije Universiteit Medical Center. Department of Clinical Genetics and Human Genetics)
Pals, Gerard (Vrije Universiteit Medical Center. Department of Clinical Genetics and Human Genetics)
Winter, Johan P. de (Vrije Universiteit Medical Center. Department of Clinical Genetics and Human Genetics)
Joenje, Hans (Vrije Universiteit Medical Center. Department of Clinical Genetics and Human Genetics)
Grompe, Markus (Oregon Health and Science University, Department of Medical and Molecular Genetics)
Auerbach, Arleen D. (The Rockefeller University. Laboratory of Human Genetics and Hematology)
Hanenberg, Helmut (University of Dusseldorf. Department of Pediatric Oncology, Hematology and Immunology)
Schindler, Detlev (University of Wurzburg. Department of Human Genetics)

Date:	2007
Abstract:	FANCD2 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.
Note:	Premi a l'excel·lència investigadora. Àmbit de les Ciències de la Salut. 2008
Rights:	Tots els drets reservats.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	PREI 2008 ; Fanconi anemia ; FANCD2 ; Hypomorphic mutations ; Splicing ; Residual protein
Published in:	American journal of human genetics, Vol. 80, Núm. 5 (2007) , p. 895-910, ISSN 0002-9297

DOI: 10.1086/517616
PMID: 17436244

Postprint 59 p, 1.7 MB

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