Defects in the cappuccino (cno) gene on mouse chromosome 5 and human 4p cause Hermansky-Pudlak syndrome by an AP-3-independent mechanism

Defects in a triad of organelles (melanosomes, platelet granules, and lysos omes) result in albinism, prolonged bleeding, and lysosome abnormalities in Hermansky-Pudlak syndrome (HPS). Defects in HPS1, a protein of unknown fun ction, 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 character ize 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 ey e and skin, resulting in severe oculocutaneous albinism. Platelet dense bod y contents (adenosine triphosphate, serotonin) are markedly deficient, lead ing to defective aggregation and prolonged bleeding. Lysosomal enzyme conce ntrations are significantly elevated in the kidney and liver. Genetic, immu nofluorescence microscopy, and lysosomal protein trafficking studies indica te that the AP-3 complex is intact in cno/cno mice, It was concluded that t he cappuccino gene encodes a product involved in an AP-3-independent mechan ism critical to the biogenesis of lysosome-related organelles. (C) 2000 by The American Society of Hematology.