Abnormal Vesicular Trafficking in Mouse Models of Hermansky–Pudlak Syndrome

Abstract

Hermansky-Pudlak Syndrome (HPS) is a group of related multigenic recessively inherited disorders which causes abnormalities in the biosynthesis and/or function of three related organelles; melanosomes, platelet-dense granules and lysosomes. These lead, in turn, to hypopigmentation, prolonged bleeding and ceroid deposition. Positional cloning strategies have identified five mouse HPS genes. Two orthologous human diseases (HPS1 and HPS2) have likewise been identified. At least four of the five mouse genes encode proteins involved in the regulation of intracellular vesicle trafficking. The pearl (HPS2) and mocha genes encode the beta3A and delta subunits, respectively, of the AP-3 adaptor complex, which captures organelle membrane proteins at the trans-Golgi apparatus. The protein products of the pallid and gunmetal genes are also important components of the vesicular trafficking machinery. The former interacts with a t-SNARE, syntaxin13, and the latter is the alpha subunit of Rab geranylgeranyltransferase, which renders Rab proteins sufficiently lipophilic to function at their target membranes. The pale ear (HPS1) gene encodes a ubiquitously expressed protein of unknown function. Recent physiological studies have shown that mouse HPS mutants, like their human HPS counterparts, have variably reduced lifespans and may have lung abnormalities.

Mutation of melanosome protein RAB38 in chocolate mice

“…Interestingly, similar to what is seen in Rab38 cht ͞Rab38 chtderived melanocytes, melanocytes from Hps1 ep ͞Hps1 ep mutants also exhibit a mislocalization of TYRP1 into membranous complexes rather than premelanosomes (38), again yielding a brown mouse. In addition to melanosome pigment defects, HPS mice exhibit enlargement of melanosomes and lysosomes and reduced platelet aggregation (27,39). This finding suggests involvement of HPS genes in early vesicle sorting events that affect both lysosomes as well as melanosomes.…”

A Genome Scan for Eye Color in 502 Twin Families: Most Variation is due to a QTL on Chromosome 15q

“…Pigmentation genes characterized to date fall into a limited number of functional groups effecting cellular processes such as melanocyte formation, development and differentiation, melanosomal components involved in enzymatic catalysis, structure or substrate transport, organelle biogenesis, cellular trafficking, and the regulatory pathway of pigment-type switching (Kushimoto et al, 2003;Marks & Seabra, 2001;Swank et al, 2000). Although the power of mouse genetics is evident in identifying genes involved in coat color, less is known about the genetics of human skin and eye color.…”

A role for Rab27b in NF-E2-dependent pathways of platelet formation

“…Other insights derive from findings in animal models of the human Hermansky-Pudlak syndrome (HPS), a multigenic group of recessively inherited disorders that result from abnormal synthesis of 3 related organelles: melanosomes, platelet-dense granules, and lysosomes. 7 HPS proteins regulate intracellular vesicle traffic, including the ␦ and ␤3A subunits of the AP-3 adaptor complex, which captures organelle membrane proteins at the trans-Golgi apparatus and/or endosomes, and the pallid protein, which interacts with syntaxin-13 to mediate vesicle fusion. 8,9 These HPS proteins highlight molecular pathways that serve to assemble and transport organelles but they do not overtly influence the efficiency with which MKs release platelets.…”