title: Cappuccino, a mouse model of Hermansky-Pudlak syndrome, encodes a novel protein that is part of the pallidin-muted complex (BLOC-1).
abstract: Hermansky-Pudlak syndrome (HPS) is a disorder of organelle biogenesis affecting 3 related organelles-melanosomes, platelet dense bodies, and lysosomes. Four genes causing HPS 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 3 distinct protein complexes: the adaptor complex AP-3; the HPS1/HPS4 complex; and BLOC-1 (biogenesis of lysosome-related organelles complex-1), consisting of the proteins encoded at 2 mouse HPS loci, pallid (pa) and muted (mu), and at least 3 other unidentified proteins. Here, we report the cloning of the mouse HPS 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 HPS and failed to identify any CNO defects. Notably, although defects in components of the HPS1/HPS4 and the AP-3 complexes are associated with HPS in humans, no defects in the known components of BLOC-1 have been identified in 142 patients with HPS screened to date, suggesting that BLOC-1 function may be critical in humans.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA. luanne@jax.org
authors.forename: Steven L
authors.initials: SL
authors.lastname: Ciciotte
authors.forename: Babette
authors.initials: B
authors.lastname: Gwynn
authors.forename: Kengo
authors.initials: K
authors.lastname: Moriyama
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.forename: Juan S
authors.initials: JS
authors.lastname: Bonifacino
authors.forename: Luanne L
authors.initials: LL
authors.lastname: Peters
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D004252:DNA Mutational Analysis; D005347:Fibroblasts; D022861:Hermanski-Pudlak Syndrome / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D014018:Tissue Distribution; D033921:Vesicular Transport Proteins
chemical_list: C475463:BLOC1S4 protein, human; C400284:BLOC1S6 protein, human; C475462:Bloc1s4 protein, mouse; C513476:Bloc1s6 protein, mouse; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D033921:Vesicular Transport Proteins