Copyright © 2007 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 80, Issue 5, 895-910, 1 May 2007
doi:10.1086/517616
Article
Hypomorphic Mutations in the Gene Encoding a Key Fanconi Anemia Protein, FANCD2, Sustain a Significant Group of FA-D2 Patients with Severe Phenotype
Reinhard Kalba, Kornelia Nevelinga, Holger Hoehn, Hildegard Schneider, Yvonne Linka, Sat Dev Batishb, Curtis Huntc, Marianne Berwickc, Elsa Callénd, e, Jordi Surrallésd, e, h, José A. Casadoe, f, Juan Buerene, f, Ángeles Dasí, Jean Soulierd, e, h, Eliane Gluckmanh, C. Michel Zwaani, Rosalina van Spaendonkj, Gerard Palsj, Johan P. de Winterj, Hans Joenjej, Markus Grompek, Arleen D. Auerbachb, Helmut Hanenberg and Detlev Schindlera, 
, 
a Department of Human Genetics, University of Wurzburg, Wurzburg, Germany
b Department of Pediatric Oncology, Hematology and Immunology, University of Dusseldorf, Dusseldorf
c Laboratory of Human Genetics and Hematology, Rockefeller University, New York
d Division of Epidemiology, University of New Mexico, Albuquerque
e Department of Genetics and Microbiology, Universitat Autónoma de Barcelona, Barcelona
f Centre for Biomedical Research on Rare Diseases, Bellaterra, Spain
g Hematopoiesis and Gene Therapy Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Madrid
h Unit of Pediatric Hematology, Hospital la Fe, Valencia
i Institut Universitaire d’Hematologie, Hôpital Saint-Louis, Paris
j Department of Pediatric Hematology/Oncology, Erasmus Medical Center–Sophia Children’s Hospital, and Dutch Childhood Oncology Group, Rotterdam
k Department of Clinical Genetics and Human Genetics, Vrije Universiteit Medical Center, Amsterdam
l Department of Medical and Molecular Genetics, Oregon Health and Science University, Portland
m and Department of Pediatrics, Indiana University School of Medicine, Indianapolis
Address for correspondence and reprints: Dr. Detlev Schindler, Department of Human Genetics, University of Wurzburg, Biozentrum, Am Hubland, D-97074 Wurzburg, Germany.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.
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