Reduced pigmentation (rp), a mouse model of Hermansky-Pudlak syndrome, encodes a novel component of the BLOC-1 complex

• Published in: Blood 2004-11, Vol.104 (10), p.3181-3189
• Main Authors: Gwynn, Babette, Martina, Jose A., Bonifacino, Juan S., Sviderskaya, Elena V., Lamoreux, M. Lynn, Bennett, Dorothy C., Moriyama, Kengo, Huizing, Marjan, Helip-Wooley, Amanda, Gahl, William A., Webb, Lisa S., Lambert, Amy J., Peters, Luanne L.
• Format: Article
• Language: English
• Subjects: Adaptor Protein Complex 3; Adaptor Protein Complex beta Subunits; Amino Acid Sequence; Animals; Biological and medical sciences; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line, Tumor; Chromosome Mapping; Cloning, Molecular; Disease Models, Animal; Female; Fibroblasts - cytology; Hematologic and hematopoietic diseases; Hermanski-Pudlak Syndrome - genetics; Hermanski-Pudlak Syndrome - physiopathology; Humans; Lysosomes - physiology; Male; Medical sciences; Melanocytes - cytology; Melanocytes - physiology; Melanoma; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Molecular Sequence Data; Nerve Tissue Proteins; Phenotype; Pigmentation - genetics; Platelet diseases and coagulopathies; Transcription Factors - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-04-1538

Hermansky-Pudlak syndrome (HPS), a disorder of organelle biogenesis, affects lysosomes, melanosomes, and platelet dense bodies. Seven genes cause HPS in humans (HPS1-HPS7) and at least 15 nonallelic mutations cause HPS in mice. Where their function is known, the HPS proteins participate in protein trafficking and vesicle docking/fusion events during organelle biogenesis. HPS-associated genes participate in at least 4 distinct protein complexes: the adaptor complex AP-3; biogenesis of lysosome-related organelles complex 1 (BLOC-1), consisting of 4 HPS proteins (pallidin, muted, cappuccino, HPS7/sandy); BLOC-2, consisting of HPS6/ruby-eye, HPS5/ruby-eye-2, and HPS3/cocoa; and BLOC-3, consisting of HPS1/pale ear and HPS4/light ear. Here, we report the cloning of the mouse HPS mutation reduced pigmentation (rp). We show that the wild-type rp gene encodes a novel, widely expressed 195-amino acid protein that shares 87% amino acid identity with its human orthologue and localizes to punctate cytoplasmic structures. Further, we show that phosphorylated RP is part of the BLOC-1 complex. In mutant rp/rp mice, a premature stop codon truncates the protein after 79 amino acids. Defects in all the 5 known components of BLOC-1, including RP, cause severe HPS in mice, suggesting that the subunits are nonredundant and that BLOC-1 plays a key role in organelle biogenesis.