title: The Hermansky-Pudlak syndrome 1 (HPS1) and HPS2 genes independently contribute to the production and function of platelet dense granules, melanosomes, and lysosomes.
abstract: Hermansky-Pudlak syndrome (HPS) is an inherited hemorrhagic disease affecting the related subcellular organelles platelet dense granules, lysosomes, and melanosomes. The mouse genes for HPS, pale ear and pearl, orthologous to the human HPS1 and HPS2 (ADTB3A) genes, encode a novel protein of unknown function and the beta(3)A subunit of the AP-3 adaptor complex, respectively. To test for in vivo interactions between these genes in the production and function of intracellular organelles, mice doubly homozygous for the 2 mutant genes were produced by appropriate breeding. Cooperation between the 2 genes in melanosome production was evident in increased hypopigmentation of the coat together with dramatic quantitative and qualitative alterations of melanosomes of the retinal pigment epithelium and choroid of double mutant mice. Lysosomal and platelet dense granule abnormalities, including hyposecretion of lysosomal enzymes from kidneys and depression of serotonin concentrations of platelet dense granules were likewise more severe in double than single mutants. Also, lysosomal enzyme concentrations were significantly increased in lungs of double mutant mice. Interaction between the 2 genes was specific in that effects on organelles were confined to melanosomes, lysosomes, and platelet dense granules. Together, the evidence indicates these 2 HPS genes function largely independently at the whole organism level to affect the production and function of all 3 organelles. Further, the increased lysosomal enzyme levels in lung of double mutant mice suggest a cause of a major clinical problem of HPS, lung fibrosis. Finally, doubly mutant HPS mice are a useful laboratory model for analysis of severe HPS phenotypes.
authors.affiliation: Diabetes Center, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Feng
authors.forename: Edward K
authors.initials: EK
authors.lastname: Novak
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Hartnell
authors.forename: Juan S
authors.initials: JS
authors.lastname: Bonifacino
authors.forename: Lucy M
authors.initials: LM
authors.lastname: Collinson
authors.forename: Richard T
authors.initials: RT
authors.lastname: Swank
mesh_terms: D033963:Adaptor Protein Complex 3; D033966:Adaptor Protein Complex beta Subunits; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D003594:Cytoplasmic Granules / Q000235:genetics / Q000502:physiology; D022162:Cytoplasmic Vesicles / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D005123:Eye / Q000473:pathology / Q000648:ultrastructure; D006026:Glycoside Hydrolases / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D020460:Melanosomes / Q000235:genetics / Q000502:physiology / Q000648:ultrastructure; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010858:Pigmentation / Q000235:genetics; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D014018:Tissue Distribution
chemical_list: C439973:AP3B1 protein, human; D033963:Adaptor Protein Complex 3; D033966:Adaptor Protein Complex beta Subunits; C491131:Hps1 protein, mouse; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D011506:Proteins; D006026:Glycoside Hydrolases