High frequency of Hermansky-Pudlak syndrome type 1 (HPS1) among Japanese albinism patients and functional analysis of HPS1 mutant protein.
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.
Ito
Shiro
S
Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Suzuki
Tamio
T
Inagaki
Katsuhiko
K
Suzuki
Noriyuki
N
Takamori
Kenji
K
Yamada
Tomoko
T
Nakazawa
Mitsuru
M
Hatano
Michihiro
M
Takiwaki
Hirotsugu
H
Kakuta
Yumi
Y
Spritz
Richard A
RA
Tomita
Yasushi
Y
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
D020662:Guanine Nucleotide Exchange Factors; C102160:HPS1 protein, human; C451752:HPS4 protein, human; D008565:Membrane Proteins; D011506:Proteins