title: Hermansky-Pudlak syndrome is caused by mutations in HPS4, the human homolog of the mouse light-ear gene.
abstract: Hermansky-Pudlak syndrome (HPS) is a disorder of organelle biogenesis in which oculocutaneous albinism, bleeding and pulmonary fibrosis result from defects of melanosomes, platelet dense granules and lysosomes. HPS is common in Puerto Rico, where it is caused by mutations in the genes HPS1 and, less often, HPS3 (ref. 8). In contrast, only half of non-Puerto Rican individuals with HPS have mutations in HPS1 (ref. 9), and very few in HPS3 (ref. 10). In the mouse, more than 15 loci manifest mutant phenotypes similar to human HPS, including pale ear (ep), the mouse homolog of HPS1 (refs 13,14). Mouse ep has a phenotype identical to another mutant, light ear (le), which suggests that the human homolog of le is a possible human HPS locus. We have identified and found mutations of the human le homolog, HPS4, in a number of non-Puerto Rican individuals with HPS, establishing HPS4 as an important HPS locus in humans. In addition to their identical phenotypes, le and ep mutant mice have identical abnormalities of melanosomes, and in transfected melanoma cells the HPS4 and HPS1 proteins partially co-localize in vesicles of the cell body. In addition, the HPS1 protein is absent in tissues of le mutant mice. These results suggest that the HPS4 and HPS1 proteins may function in the same pathway of organelle biogenesis.
authors.affiliation: Human Medical Genetics Program, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
authors.forename: Tamio
authors.initials: T
authors.lastname: Suzuki
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Amna
authors.initials: A
authors.lastname: Karim
authors.forename: Edward K
authors.initials: EK
authors.lastname: Novak
authors.forename: Elena V
authors.initials: EV
authors.lastname: Sviderskaya
authors.forename: Simon P
authors.initials: SP
authors.lastname: Hill
authors.forename: Dorothy C
authors.initials: DC
authors.lastname: Bennett
authors.forename: Alex V
authors.initials: AV
authors.lastname: Levin
authors.forename: H Karel
authors.initials: HK
authors.lastname: Nieuwenhuis
authors.forename: Chin-To
authors.initials: CT
authors.lastname: Fong
authors.forename: Claudio
authors.initials: C
authors.lastname: Castellan
authors.forename: Bianca
authors.initials: B
authors.lastname: Miterski
authors.forename: Richard T
authors.initials: RT
authors.lastname: Swank
authors.forename: Richard A
authors.initials: RA
authors.lastname: Spritz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D005455:Fluorescent Antibody Technique; D020662:Guanine Nucleotide Exchange Factors; D022861:Hermanski-Pudlak Syndrome / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C451752:HPS4 protein, human; D011506:Proteins