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

Wei Li, Qing Zhang, Naoki Oiso, Edward K. Novak, Rashi Gautam, Edward P. O'Brien, Caroline L. Tinsley, Derek J. Blake, Richard A. Spritz, Neal G. Copeland, Nancy A. Jenkins, Dominick Amato, Bruce A. Roe, Marta Starcevic, Esteban C. Dell'Angelica, Rosemary W. Elliott, Vishnu Mishra, Stephen F. Kingsmore, Richard E. Paylor, Richard T. Swank

Research output: Contribution to journalArticle

345 Scopus citations

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. In mice, at least 16 loci are associated with HPS4, 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 cells. 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.

Original languageEnglish (US)
Pages (from-to)84-89
Number of pages6
JournalNature Genetics
Volume35
Issue number1
DOIs
StatePublished - Sep 1 2003

ASJC Scopus subject areas

  • Genetics

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