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Blood, 15 December 2000, Vol. 96, No. 13, pp. 4227-4235
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Defects in the cappuccino (cno) gene on mouse
chromosome 5 and human 4p cause Hermansky-Pudlak syndrome by an
AP-3-independent mechanism
Babette Gwynn,
Steven L. Ciciotte,
Susan J. Hunter,
Linda L. Washburn,
Richard S. Smith,
Sabra G. Andersen,
Richard T. Swank,
Esteban C. Dell'Angelica,
Juan S. Bonifacino,
Eva M. Eicher, and
Luanne L. Peters
From the The Jackson Laboratory, Bar Harbor, ME;
Department of Biological Sciences, University of Maine, Orono, ME;
Department of Molecular and Cellular Biology, Roswell Park Cancer
Institute, Buffalo, NY, and Cell Biology and Metabolism Branch,
National Institute of Child Health and Human Development, National
Institutes of Health, Bethesda, MD.
Defects in a triad of organelles (melanosomes, platelet granules,
and lysosomes) result in albinism, prolonged bleeding, and lysosome
abnormalities in Hermansky-Pudlak syndrome (HPS). Defects in HPS1, a
protein of unknown function, and in components of the AP-3 complex
cause some, but not all, cases of HPS in humans. There have been 15 inherited models of HPS described in the mouse, underscoring its marked
genetic heterogeneity. Here we characterize a new spontaneous
mutation in the mouse, cappuccino (cno), that maps to mouse
chromosome 5 in a region conserved with human 4p15-p16. Melanosomes of
cno/cno mice are immature and dramatically decreased in
number in the eye and skin, resulting in severe oculocutaneous albinism. Platelet dense body contents (adenosine triphosphate, serotonin) are markedly deficient, leading to defective aggregation and
prolonged bleeding. Lysosomal enzyme concentrations are significantly elevated in the kidney and liver. Genetic, immunofluorescence microscopy, and lysosomal protein trafficking studies indicate that the
AP-3 complex is intact in cno/cno mice. It was concluded that the cappuccino gene encodes a product involved in an
AP-3-independent mechanism critical to the biogenesis of
lysosome-related organelles.
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