Nature Genetics
36, 1219 - 1224 (2004)
Published online: 24 October 2004; | doi:10.1038/ng1458
X-linked inheritance of Fanconi anemia complementation group BAmom Ruhikanta Meetei1, 5, Marieke Levitus2, 5, Yutong Xue1, Annette L Medhurst2, Michel Zwaan3, Chen Ling1, Martin A Rooimans2, Patrick Bier2, Maureen Hoatlin4, Gerard Pals2, Johan P de Winter2, Weidong Wang1
& Hans Joenje21
Laboratory of Genetics, National Institute on Aging, National Institutes of Health, 333 Cassell Drive, TRIAD Center Room 3000, Baltimore, Maryland 21224, USA. 2
Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. 3
Department of Pediatrics and Hematology/Oncology, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands. 4
Division of Molecular Medicine & Molecular and Medical Genetics/Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA. 5
These authors contributed equally to this work.
Correspondence should be addressed to Weidong Wang wangw@grc.nia.nih.gov or Hans Joenje joenje@vumc.nlFanconi anemia is an autosomal recessive syndrome characterized by diverse clinical symptoms, hypersensitivity to DNA crosslinking agents, chromosomal instability and susceptibility to cancer1,
2. Fanconi anemia has at least 11 complementation groups (A, B, C, D1, D2, E, F, G, I, J, L)3,
4; the genes mutated in 8 of these have been identified. The gene BRCA2 was suggested to underlie complementation group B, but the evidence is inconclusive5. Here we show that the protein defective in individuals with Fanconi anemia belonging to complementation group B is an essential component of the nuclear protein 'core complex' responsible for monoubiquitination of FANCD2, a key event in the DNA-damage response pathway associated with Fanconi anemia and BRCA3,
6,
7. Unexpectedly, the gene encoding this protein, FANCB, is localized at Xp22.31 and subject to X-chromosome inactivation. X-linked inheritance has important consequences for genetic counseling of families with Fanconi anemia belonging to complementation group B. Its presence as a single active copy and essentiality for a functional Fanconi anemia−BRCA pathway make FANCB a potentially vulnerable component of the cellular machinery that maintains genomic integrity.
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