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

  1. Author:
    Li, W.
    Zhang, Q.
    Oiso, N.
    Novak, E. K.
    Gautam, R.
    O'Brien, E. P.
    Tinsley, C. L.
    Blake, D. J.
    Spritz, R. A.
    Copeland, N. G.
    Jenkins, N. A.
    Amato, D.
    Roe, B. A.
    Starcevic, M.
    Dell'Angelica, E. C.
    Elliott, R. W.
    Mishra, V.
    Kingsmore, S. F.
    Paylor, R. E.
    Swank, R. T.

  2. Author Address

    Roswell Pk Canc Inst, Dept Mol & Cellular Biol, Buffalo, NY 14263 USA Roswell Pk Canc Inst, Dept Mol & Cellular Biol, Buffalo, NY 14263 USA Univ Colorado, Hlth Sci Ctr, Human Med Genet Program, Denver, CO 80262 USA Univ Oxford, Dept Pharmacol, Oxford OX1 3QT, England NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA Univ Toronto, Dept Med, Div Hematol & Med Oncol, Toronto, ON M5G 1X5, Canada Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada Univ Oklahoma, Dept Chem & Biochem, Norman, OK 73019 USA Univ Calif Los Angeles, Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA Univ Florida, Dept Med, Gainesville, FL 32610 USA Mol Staging, New Haven, CT 06511 USA Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA Swank RT Roswell Pk Canc Inst, Dept Mol & Cellular Biol, Buffalo, NY 14263 USA
    1. Year: 2003
  2. Journal: Nature Genetics
    1. 35
    2. 1
    3. Pages: 84-89
  4. Type of Article: Article
  1. 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 granules(1- 3). In mice, at least 16 loci are associated with HPS4-6, 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 alpha- and beta-dystrobrevins, components of the dystrophin- associated protein complex (DPC) in both muscle and nonmuscle cells(8). We also show that dysbindin is a component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1; refs. 9-11), 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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