Comment on Gwynn et al, page 3181

An article in this issue of Blood provides genetic and molecular insights into a critical but relatively little understood aspect of platelet physiology, that is, the biosynthesis of platelet dense granules.

Gwynn and colleagues use a positional cloning approach to identify the gene mutated in the reduced pigment (rp) mouse, a model for human Hermansky-Pudlak syndrome (HPS). HPS is a genetically heterogeneous disease whose symptoms (prolonged bleeding, light or hypopigmentation, and lung fibrosis) arise from defective biogenesis and/or trafficking of lysosome-related organelles including platelet dense granules, melanosomes, and lamellar bodies of lung type II cells, respectively.1  The rp gene encodes a novel, widely expressed 195–amino acid protein. The novel nature of the rp gene is a recurring theme among 10 recently identified HPS genes.

All 10 novel HPS proteins interact within 3 distinct ubiquitously expressed protein complexes or biogenesis of lysosome-related organelle complexes (BLOCs). Gwynn and colleagues show that the rp protein coimmunoprecipitates with the pallidin, cappuccino, and muted HPS proteins, indicating that it is a component of the BLOC-1 complex, perhaps the best characterized of the 3 HPS BLOCs. Dell'Angelica et al2  have independently identified the rp mutation and the residence of its encoded protein within BLOC-1. Additionally they have used proteomic approaches to define 3 additional BLOC-1 components, the novel proteins BLOC subunits 1 and 2 (BLOS1 and BLOS2) together with the coiled-coil protein, Snapin. Altogether then BLOC-1 contains 7 novel proteins, and mutations in at least 5 of them produce HPS in mice. The fact that the phenotypes of BLOC-1 mutants are the most severe of all mouse HPS mutants suggests that this complex plays a major role in the biogenesis of platelet dense granules and other specialized lysosome-related organelles of metazoans.

These exciting findings provide an entry for determining of the molecular mechanisms used by BLOCs to control the biosynthesis and intracellular movement of lysosome-related organelles. Missing or significant reductions in numbers of platelet dense granules is a hallmark of HPS in humans and animal models. Genes such as rp will therefore provide valuable insights into the synthesis and trafficking of this organelle, which is critical for normal platelet aggregation and function. One possible clue to the mechanism is the finding of Gwynn and colleagues that the rp protein in BLOC-1 is phosphorylated.

These and related findings give an indepth view of the mutations and genes involved in the genesis of HPS that will hopefully lead to therapies for this inherited, presently incurable disease.

Li W, Rosiniak ME, Chintala S, Gautam R, Novak EK, and Swank RT. Murine Hermansky-Pudlak syndrome: regulators of lysosome-related organelles.
Starcevic M and Dell'Angelica EC. Identification of snapin and three novel proteins (BLOS1, BLOS2, and BLOS3/reduced pigmentation) as subunits of biogenesis of lysosome-related organelles complex–1 (BLOC1).
J Biol Chem
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