Letter | Published:

Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1)

Nature Genetics 35, 84–89 (2003) | Download Citation

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Abstract

Hermansky-Pudlak syndrome (HPS; MIM 203300) is a genetically heterogeneous disorder characterized by oculocutaneous albinism, prolonged bleeding and pulmonary fibrosis due to abnormal vesicle trafficking to lysosomes and related organelles, such as melanosomes and platelet dense granules1,2,3. In mice, at least 16 loci are associated with HPS4,5,6, including sandy (sdy; ref. 7). Here we show that the sdy mutant mouse expresses no dysbindin protein owing to a deletion in the gene Dtnbp1 (encoding dysbindin) and that mutation of the human ortholog DTNBP1 causes a novel form of HPS called HPS-7. Dysbindin is a ubiquitously expressed protein that binds to α- and β-dystrobrevins, components of the dystrophin-associated protein complex (DPC) in both muscle and nonmuscle cells8. We also show that dysbindin is a component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1; refs. 9,​10,​11), which regulates trafficking to lysosome-related organelles and includes the proteins pallidin, muted and cappuccino, which are associated with HPS in mice. These findings show that BLOC-1 is important in producing the HPS phenotype in humans, indicate that dysbindin has a role in the biogenesis of lysosome-related organelles and identify unexpected interactions between components of DPC and BLOC-1.

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GenBank/EMBL/DDBJ

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Acknowledgements

We thank D. Reddington, L. Zhen, Y. Jiang, D. Poslinski, D. Tabaczynski, M.K. Ellsworth, J. Tan, H. Chen and X. Hu for technical assistance. M. Pagan contributed to the construction of the sdy genetic map. This work was supported in part by grants from the US National Institutes of Health (R.T.S., R.W.E., R.A.S., E.C.D. and B.A.R.) and by the National Cancer Institute, US Department of Health and Human Services (N.G.C. and N.A.J.). D.J.B. is a Wellcome Trust Senior Fellow. This research used core facilities supported in part by Cancer Center Support Grant to Roswell Park Cancer Institute funded by the National Cancer Institute.

Author information

    • Wei Li
    • , Qing Zhang
    •  & Naoki Oiso

    These authors contributed equally to this work.

Affiliations

  1. Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

    • Wei Li
    • , Qing Zhang
    • , Edward K Novak
    • , Rashi Gautam
    • , Edward P O'Brien
    • , Rosemary W Elliott
    •  & Richard T Swank

  2. Human Medical Genetics Program, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.

    • Naoki Oiso
    •  & Richard A Spritz

  3. Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.

    • Caroline L Tinsley
    •  & Derek J Blake

  4. Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland 21702, USA.

    • Neal G Copeland
    •  & Nancy A Jenkins

  5. Department of Medicine, Division of Medical Oncology and Hematology, University of Toronto and Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.

    • Dominick Amato

  6. Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, USA.

    • Bruce A Roe

  7. Department of Human Genetics, UCLA School of Medicine, Los Angeles, California 90095, USA.

    • Marta Starcevic
    •  & Esteban C Dell'Angelica

  8. Department of Medicine, University of Florida, Gainesville, Florida 32610, USA.

    • Vishnu Mishra

  9. Molecular Staging, New Haven, Connecticut 06511, USA.

    • Stephen F Kingsmore

  10. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.

    • Richard E Paylor

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Richard T Swank.

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DOI

https://doi.org/10.1038/ng1229