X-linked inheritance of Fanconi anemia complementation group B

• Published in: Nature genetics Vol. 36; no. 11; pp. 1219 - 1224
• Main Authors: Meetei, Amom Ruhikanta, Levitus, Marieke, Xue, Yutong, Medhurst, Annette L, Zwaan, Michel, Ling, Chen, Rooimans, Martin A, Bier, Patrick, Hoatlin, Maureen, Pals, Gerard, de Winter, Johan P, Wang, Weidong, Joenje, Hans
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2004; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; Biological and medical sciences; Biomedicine; Breast cancer; Cancer Research; Chromosome fragility (bloom syndrome, ataxia telangiectasia, fanconi anemia, x-linked mental retardation...); Chromosomes, Human, X; Complementation (Genetics); Complex syndromes; Complications and side effects; Deoxyribonucleic acid; Diagnosis; DNA; DNA Methylation; Dosage Compensation, Genetic; Fanconi Anemia - genetics; Fanconi Anemia Complementation Group D2 Protein; Fanconi's anemia; Female; Fundamental and applied biological sciences. Psychology; Gene Function; Gene mutations; Genetic aspects; Genetic Complementation Test; Genetic Linkage; Genetic screening; Genetics of eukaryotes. Biological and molecular evolution; Human Genetics; Humans; Hypersensitivity; Inactivation; letter; Male; Medical genetics; Medical sciences; Mutation; Nuclear Proteins - metabolism; Pedigree; Physiological aspects; Receptors, Androgen - metabolism; Risk factors; United States; Chromosome fragility; Sex linked character; Fanconi anemia; Hypersensitivity; Hemopathy; Autosome; Essential; Syndrome; Genetic disease; BRCA2 gene; DNA; Instability; Complementation; X-Chromosome; Inheritance(genetics); Nuclear protein; Tumor suppressor gene
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1458

Fanconi anemia is an autosomal recessive syndrome characterized by diverse clinical symptoms, hypersensitivity to DNA crosslinking agents, chromosomal instability and susceptibility to cancer 1 , 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 inconclusive 5 . 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 BRCA 3 , 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.