Cappuccino, a mouse model of Hermansky-Pudlak syndrome, encodes a novel protein that is part of the pallidin-muted complex (BLOC-1)

Hermansky-Pudlak syndrome (HIPS) is a disorder of organelle biogenesis affecting 3 related organelles-melanosomes, platelet dense bodies, and lysosomes. Four genes causing HIPS in humans (HPS1-HPS4) are known, and at least 15 nonallelic mutations cause HPS in the mouse. Where their functions are known, the HPS-associated proteins are involved in, some aspect of intracellular vesicular trafficking, that is, protein sorting and vesicle docking and fusion. Biochemical and genetic evidence indicates that the HPS-associated genes encode components of at least distinct protein complexes: the adaptor complex AP-3; the HPS1/HPS4 complex; and BLOC-1 (bio-genesis of lysosome-related organelles complex-1), consisting of the proteins encoded at mouse HPS loci, pallid(pa) and muted (mu), and at least 3 other unidentified proteins. Here, we report the cloning of the mouse HIPS mutation cappuccino, (cno). We show that the wild-type cno gene encodes a novel, ubiquitously expressed cytoplasmic protein that coassembles With pallidin and the muted protein in the BLOC-1 complex. Further, we identify a frameshift mutation in mutant cno/cno mice. The C-terminal 81 amino acids are replaced with 72 different amino acids in the mutant CNO protein, and its ability to interact in BLOC-1 is abolished. We performed mutation screening of patients with HP and failed to identify any CNO defects. Notably, although defects in components of the HPS1/HPS4 and the AP-3 complexes are associated with HIPS in humans, no defects in the known components of BLOC-1 have been identified in 142 patients with HIPS screened to date, suggesting that BLOC-1 function may be critical in humans. (C) 2003 by The American Society of Hematology.