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X-linked inheritance of Fanconi anemia complementation group B

Nature Genetics volume 36, pages 1219–1224 (2004)Cite this article

Abstract

Fanconi 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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Figure 1: FANCB is a member of the core complex required for monoubiquitination of FANCD2.
Figure 2: Nuclear localization of FAAP95 depends on FANCA.
Figure 3: Evidence of a genetic defect in FAAP95 in individuals with FA-B.
Figure 4: Pedigrees of the four families with FA-B.
Figure 5: Hemizygosity and heterozygosity of mutations in FANCB.
Figure 6: FANCB is subject to X inactivation that is skewed towards the mutated allele in heterozygous carriers of the FANCB mutation.

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Acknowledgements

We thank the individuals and families with Fanconi anemia for contributing to this study, R. Dietrich for collecting blood and tissue samples, M. Buchwald for providing the HSC230 and HSC231 cell lines, N. Sherman for mass spectrometry analysis, J. Steltenpool and A.B. Oostra for technical assistance, R. Vervenne for suggestions, H. Willard and Q. Waisfisz for communicating unpublished results, D. Schlessinger for critically reading the manuscript and the National Cell Culture Center for providing cells. Financial support was from the Dutch Cancer Society, The Netherlands Organization for Health Research and Development, the FA Research Fund Inc., the Ellison medical Foundation, the US National Institutes of Health and the Deutsche FA Hilfe e.V.

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Author notes

  1. Amom Ruhikanta Meetei and Marieke Levitus: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Genetics, National Institute on Aging, National Institutes of Health, 333 Cassell Drive, TRIAD Center Room 3000, Baltimore, 21224, Maryland, USA

    Amom Ruhikanta Meetei, Yutong Xue, Chen Ling & Weidong Wang

  2. Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, Amsterdam, 1081 BT, The Netherlands

    Marieke Levitus, Annette L Medhurst, Martin A Rooimans, Patrick Bier, Gerard Pals, Johan P de Winter & Hans Joenje

  3. Department of Pediatrics and Hematology/Oncology, VU University Medical Center, PO Box 7057, Amsterdam, 1007 MB, The Netherlands

    Michel Zwaan

  4. Division of Molecular Medicine & Molecular and Medical Genetics/Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, 97239, Oregon, USA

    Maureen Hoatlin

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  1. Amom Ruhikanta Meetei
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Corresponding authors

Correspondence to Weidong Wang or Hans Joenje.

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Supplementary information

Supplementary Fig. 1

Human and mouse FANCB proteins contain a nuclear-localization sequence near the C-terminus. (PDF 62 kb)

Supplementary Fig. 2

A control experiment for FANCA-dependent nuclear localization of FAAp95. (PDF 3 kb)

Supplementary Fig. 3

FAAP95 cDNA partially complemented the HSC230 cell line for its MMC-hypersensitivity. (PDF 112 kb)

Supplementary Fig. 4

FANCB is subject to X inactivation which is skewed towards the mutated allele in heterozygous FANCB mutation carriers. (PDF 2 kb)

Supplementary Table 1

Clinical symptoms of 4 FA-B patients. (PDF 2 kb)

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Meetei, A., Levitus, M., Xue, Y. et al. X-linked inheritance of Fanconi anemia complementation group B. Nat Genet 36, 1219–1224 (2004). https://doi.org/10.1038/ng1458

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