Nature Genetics
35, 84 - 89 (2003)
Published online: 17 August 2003; | doi:10.1038/ng1229
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 Li1, 11, Qing Zhang1, 11, Naoki Oiso2, 11, Edward K Novak1, Rashi Gautam1, Edward P O'Brien1, Caroline L Tinsley3, Derek J Blake3, Richard A Spritz2, Neal G Copeland4, Nancy A Jenkins4, Dominick Amato5, Bruce A Roe6, Marta Starcevic7, Esteban C Dell'Angelica7, Rosemary W Elliott1, Vishnu Mishra8, Stephen F Kingsmore9, Richard E Paylor10
& Richard T Swank11
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. 2
Human Medical Genetics Program, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. 3
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK. 4
Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland 21702, USA. 5
Department of Medicine, Division of Medical Oncology and Hematology, University of Toronto and Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. 6
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, USA. 7
Department of Human Genetics, UCLA School of Medicine, Los Angeles, California 90095, USA. 8
Department of Medicine, University of Florida, Gainesville, Florida 32610, USA. 9
Molecular Staging, New Haven, Connecticut 06511, USA. 10
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA. 11
These authors contributed equally to this work.
Correspondence should be addressed to Richard T Swank richard.swank@roswellpark.orgHermansky-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  - and  -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. 9−11), 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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