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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)

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. 911), 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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Figure 1: High-resolution genetic and physical maps of the sdy gene region of mouse chromosome 13.
Figure 2: Dtnbp1 mRNA is smaller and dysbindin is undetectable in tissues of sdy mutant mice.
Figure 3: Destabilization of the dysbindin, pallidin and muted proteins in extracts of three HPS mutants (sdy, pa and mu).
Figure 4: Association of dysbindin with muted, pallidin and β-dystrobrevin.
Figure 5: Dysbindin and pallidin are components of a common protein complex in mouse liver.
Figure 6: Retinal melanosomes are deficient and abnormal in sdy mice.

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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.

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Correspondence to Richard T Swank.

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Li, W., Zhang, Q., Oiso, N. et al. Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Nat Genet 35, 84–89 (2003). https://doi.org/10.1038/ng1229

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