title: High frequency of Hermansky-Pudlak syndrome type 1 (HPS1) among Japanese albinism patients and functional analysis of HPS1 mutant protein.
abstract: Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism (OCA), bleeding tendency, and lysosomal accumulation of ceroid-like material. Seven genetically distinct subtypes of HPS are known in humans; most are rare outside of Puerto Rico. Here, we describe the analysis of the HPS1 gene in 24 Japanese OCA patients who lacked mutations in the four genes known to cause OCA (TYR/OCA1, P/OCA2, TYRP1/OCA3, and MATP/OCA4), and the identification of eight different HPS1 mutations in ten of these patients, four of which were novel (W583X, L668P, 532insC, 1691delA). An IVS5+5G --> A splice consensus mutation was particularly frequent, the result of a founder effect for this allele in Japanese patients. Functional analysis by transfection of the L668P variant into Hps1-mutant melan-ep mouse melanocytes showed that this missense substitution is pathologic, resulting in an Hps-1 protein that is unable to assemble into the biogenesis of lysosome-related organelles complex-3.
authors.affiliation: Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Ito
authors.forename: Tamio
authors.initials: T
authors.lastname: Suzuki
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Inagaki
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Suzuki
authors.forename: Kenji
authors.initials: K
authors.lastname: Takamori
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamada
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Nakazawa
authors.forename: Michihiro
authors.initials: M
authors.lastname: Hatano
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Takiwaki
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kakuta
authors.forename: Richard A
authors.initials: RA
authors.lastname: Spritz
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Tomita
mesh_terms: D000417:Albinism / Q000235:genetics*; D000818:Animals; D005260:Female; D020662:Guanine Nucleotide Exchange Factors; D006239:Haplotypes; D022861:Hermanski-Pudlak Syndrome / Q000235:genetics*; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000737:chemistry; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D009154:Mutation; D010641:Phenotype; D011506:Proteins / Q000235:genetics
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C102160:HPS1 protein, human; C451752:HPS4 protein, human; D008565:Membrane Proteins; D011506:Proteins