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Blood, 1 March 2002, Vol. 99, No. 5, pp. 1651-1658
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
The Hermansky-Pudlak syndrome 1 (HPS1) and HPS2 genes
independently contribute to the production and function of platelet
dense granules, melanosomes, and lysosomes
Lijun Feng,
Edward K. Novak,
Lisa M. Hartnell,
Juan S. Bonifacino,
Lucy M. Collinson, and
Richard T. Swank
From the Diabetes Center, Albert Einstein College of
Medicine, Bronx, New York; Department of Molecular and Cellular
Biology, Roswell Park Cancer Institute, Buffalo, New York; Cell Biology
and Metabolism Branch at the National Institute of Child Health and
Human Development, National Institutes of Health, Bethesda, Maryland;
and Department of Biochemistry, Faculty of Life Sciences, Imperial
College, London, United Kingdom.
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
 3A 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.
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