Alternative titles; symbols
HGNC Approved Gene Symbol: HPS1
Cytogenetic location: 10q24.2 Genomic coordinates (GRCh38) : 10:98,413,948-98,446,935 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q24.2 | Hermansky-Pudlak syndrome 1 | 203300 | Autosomal recessive | 3 |
Oh et al. (1996) identified the HPS1 gene by positional cloning. The HPS1 gene encodes a novel transmembrane protein that is thought to be a component of multiple cytoplasmic organelles and is apparently crucial for their normal development and function.
Wildenberg et al. (1998) demonstrated an apparent alternative transcript of the HPS1 gene. By RT-PCR and Northern blot analysis, 2 polyadenylated transcripts were found in normal human melanocytes, human bone marrow cells, human melanoma cells, lymphoblastoid cell lines, and megakaryocytic leukemia cells. Thus, the HPS1 gene is complex and may have more than 1 biologically active transcript. Wildenberg et al. (1998) noted that the same type of alternative splicing occurs in the IGHM gene (147020), resulting in membrane-bound and secreted protein products.
Martina et al. (2003) determined that HPS1 and HPS4 (606682) form a lysosomal complex that they termed BLOC3 (biogenesis of lysosome-related organelles complex-3). Coimmunoprecipitation experiments demonstrated that epitope-tagged and endogenous HPS1 and HPS4 proteins assembled with each other in vivo. The complex was predominantly cytosolic, with a small amount peripherally associated with membranes. Size exclusion chromatography and sedimentation velocity analysis of the cytosolic fraction indicated that HPS1 and HPS4 formed a moderately asymmetric complex with a molecular mass of about 175 kD. Hps4-deficient fibroblasts from light ear mice displayed normal distribution and trafficking of a lysosomal protein and an apparently normal accumulation of Zn(2+) in intracellular vesicles. In contrast, fibroblasts of AP3 (see AP3B1; 603401)-deficient pearl mice showed deficits in both of these measures. Martina et al. (2003) concluded that HPS1 and HPS4 are components of a cytosolic complex that is involved in the biogenesis of lysosomal-related organelles through a mechanism distinct from that operated by the AP3 complex.
Fukai et al. (1995) used the linkage disequilibrium mapping approach to localize the HPS1 locus in 2 groups in whom the Hermansky-Pudlak syndrome (203300) is particularly frequent: a group in Puerto Rico and a group in an isolated village in the Swiss Alps. They localized the HPS1 locus in both groups to a 0.6-cM interval in chromosome segment 10q23.1-q23.2. Wildenberg et al. (1995) likewise mapped the HPS1 locus to 10q. They collected blood samples from a relatively homogeneous population in Puerto Rico, where Hermansky-Pudlak syndrome has a frequency of about 1 in 1,800, giving a carrier frequency estimated to be 1 in 21. Analysis of pooled DNA samples allowed them to screen the genome rapidly for candidate loci and identify linkage with a marker on 10q. The result was verified with additional markers, and a maximum lod score of 5.07 at theta = 0.001 was calculated for marker D10S198. Haplotype analysis placed the HPS1 locus in a region of approximately 1 cM that contains the markers D10S198 and D10S1239.
Oh et al. (1996) identified homozygous frameshifts in the HPS1 gene in Puerto Rican, Swiss, Irish, and Japanese patients with Hermansky-Pudlak syndrome (HPS1; 203300).
Oh et al. (1998) performed mutation analysis on 44 unrelated Puerto Rican and 24 unrelated non-Puerto Rican HPS patients. A 16-bp frameshift duplication (604982.0001), the result of an apparent founder effect, was nearly ubiquitous among Puerto Rican patients. A frameshift at codon 322 may be the most frequent HPS mutation in Europeans. The mutation in these cases was a 1-bp insertion (or duplication) in a poly(C) tract at codons 322 to 324. Oh et al. (1998) also described 6 novel HPS1 mutations: a 5-prime splice-junction mutation of IVS5, 3 frameshifts, a nonsense mutation, and a 1-codon in-frame deletion. These mutations defined an apparent frameshift hotspot at codons 321-322. Overall, however, they detected mutations in the HPS1 gene in only about half of non-Puerto Rican patients, and presented evidence suggesting locus heterogeneity for HPS.
The different clinical phenotypes in HPS1 associated with different frameshifts in the HPS1 gene suggested to Oh et al. (1996) that differentially truncated HPS1 polypeptides may have somewhat different consequences for subcellular function.
Two genetically distinct mouse loci, 'pale ear' (ep) and 'ruby-eye' (ru), both with mutant phenotypes similar to human Hermansky-Pudlak syndrome, map close together in the homologous region of murine chromosome 19, which suggested that one of these loci might be homologous to human HPS. Feng et al. (1997) characterized the mouse Hps cDNA and genomic locus, and identified pathologic Hps gene mutations in ep but not in ru mice, establishing mouse 'pale ear' as an animal model for human Hermansky-Pudlak syndrome. The phenotype of homozygous ep mutant mice encompasses those of both Hermansky-Pudlak syndrome and Chediak-Higashi syndrome, suggesting that these disorders may be closely related. In addition, the mouse and human HPS genes both contain a rare 'AT-AC' intron (i.e., an intron with nonconsensus splice sites), and comparison of the sequences of this intron in the mouse and human genes identified conserved sequences that suggest a possible role for pre-mRNA secondary structure in excision of this rare class of introns. (See 601428 and 601429 for a discussion of small nuclear RNAs necessary for AT-AC intron splicing, and see Hall and Padgett (1994) for a discussion of introns with nonconsensus splice sites.)
To test for in vivo interactions between the HPS1 and HPS2 genes in the production and function of intracellular organelles, Feng et al. (2002) created mice doubly heterozygous for the 2 mutant genes by appropriate breeding. Cooperation between the 2 genes in melanosome production was evident in increased hypopigmentation of the coat together with dramatic quantitative and qualitative alterations of melanosomes of the retinal pigment epithelium and choroid of double-mutant mice. Lysosomal and platelet dense granule abnormalities, including hyposecretion of lysosomal enzymes from kidneys and depression of serotonin concentrations of platelet dense granules were likewise more severe in double than in single mutants. Also, lysosomal enzyme concentrations were significantly increased in lungs of double-mutant mice. Interaction between the 2 genes was specific in that effects on organelles were confined to melanosomes, lysosomes, and platelet dense granules. Together, the evidence indicated that these 2 HPS genes function largely independently at the whole-organism level to affect the production and function of all 3 organelles. Furthermore, the increased lysosomal enzyme levels in lung of double-mutant mice suggested a cause of a major clinical problem of Hermansky-Pudlak syndrome, lung fibrosis.
By SSCP/heteroduplex analysis and DNA sequencing, Oh et al. (1996) found that 22 Puerto Rican patients with Hermansky-Pudlak syndrome (HPS1; 203300) were homozygous for a 16-bp duplication within exon 15 of the HPS gene, resulting in a frameshift distal to codon pro496, with termination of the nonsense polypeptide at codon 586. Similarly, they found that all 11 obligate heterozygotes tested were heterozygous for the mutation. They did not observe this mutation in 5 Puerto Rican or 15 Asian controls, or in 11 non-Puerto Rican Hermansky-Pudlak syndrome patients. Although Hermansky-Pudlak syndrome is frequent on the island of Puerto Rico, it has not been reported elsewhere in the Caribbean. Apparent homogeneity of the 16-bp frameshift duplication among Puerto Rican Hermansky-Pudlak syndrome patients suggests that this mutation arose in Puerto Rico during its early population or colonization and that the frequency of the mutation was amplified as a founder effect due to occult inbreeding and genetic drift. The mutation was easily identified, even by simple agarose electrophoresis of the exon 15 PCR product, which appears abnormally large; furthermore, heterozygotes additionally exhibit a prominent aberrant heteroduplex band. Thus, diagnosis, prenatal diagnosis, and carrier testing for Hermansky-Pudlak syndrome in the Puerto Rican population, in which the expected frequency of heterozygote may be as high as 1 in 21 persons, is possible.
Gahl et al. (1998) stated that all identified patients with Hermansky-Pudlak syndrome in northwest Puerto Rico were found to be homozygous for the 16-bp duplication in exon 15 of the HPS gene. Gahl et al. (1998) compared the clinical and laboratory characteristics of these patients with those of patients without the 16-bp duplication. They studied 49 patients: 27 Puerto Ricans and 22 patients from mainland United States who were not of Puerto Rican descent. The diagnosis was based on the presence of albinism and the absence of platelet dense bodies. Homozygosity for the 16-bp duplication was found in 25 of the 27 Puerto Rican patients, whereas none of the non-Puerto Rican patients carried this mutation. Like the patients without the duplication, the patients with the 16-bp duplication had a broad variation in pigmentation. Nine of 16 adults with the duplication, but none of the 10 without it, had a diffusing capacity for carbon monoxide that was less than 80% of the predicted value. High-resolution computed tomography in all 12 patients with the 16-bp duplication revealed minimal fibrosis in 8, moderate fibrosis in 1, severe fibrosis in 1, and no fibrosis in 2. Computed tomography in 8 patients without the duplication revealed minimal fibrosis in 3 and no fibrosis in the rest. Inflammatory bowel disease developed in 8 patients (4 in each group) between 3 and 25 years of age. Thus, the 16-bp duplication in exon 15 of the HPS gene, which had been found only in Puerto Rican patients, is associated with a broad range of pigmentation and an increased risk of restrictive lung disease in adults.
In a patient from the inbred Swiss kindred with Hermansky-Pudlak syndrome (HPS1; 203300) studied by Schallreuter et al. (1993) and in an Irish-German HPS patient, Oh et al. (1996) identified homozygosity for a frameshift mutation due to an additional cytosine in a run of 8 cytosines in the HPS gene. Oh et al. (1998) reported this mutation as T322insC and found that the 2 patients were divergent for intragenic polymorphisms that flank the mutation; the findings suggested that the frameshift arose independently in the 2 populations. A French patient was found to be homozygous for the frameshift mutation and for the polymorphic haplotype found in the patient of Irish-German origin, and a Scottish patient was found to be compound heterozygous for the frameshift mutation with the haplotype found in the Irish-German patient and a novel glu666-to-ter (E666X; 604982.0003) nonsense mutation.
In a Scottish patient with Hermansky-Pudlak syndrome (HPS1; 203300), Oh et al. (1998) found compound heterozygosity for the T322insC frameshift mutation (604982.0002) and a novel glu666-to-ter (E666X) nonsense mutation.
In a Japanese patient with Hermansky-Pudlak syndrome (HPS1; 203300), Oh et al. (1998) identified homozygosity for a novel frameshift mutation in the HPS gene, T322delC, that involved the same poly(C) tract involved in the T322insC frameshift (604982.0002).
Shotelersuk et al. (1998) studied 18 non-Puerto Rican Hermansky-Pudlak syndrome (HPS1; 203300) families and identified HPS mutations in 3 of them. In 1 patient, a novel glu133-to-ter (E133X) mutation was present in compound state with the previously described T322insC mutation (604982.0002). The patient was a 6-year-old girl of Italian, German, and Ukrainian ancestry. Born with pale skin, she was noted to have nystagmus at 2 months of age and pale retinas at 3 months of age, when oculocutaneous albinism was diagnosed. Bruising began at 7 to 8 months of age, and Hermansky-Pudlak syndrome was diagnosed at 18 months of age based on abnormal platelet aggregation studies. Epistaxis occurred in the winter months, and prolonged bleeding accompanied a cut lip and placement of myringotomy tubes. Asthma was diagnosed at 1 year of age. There were no signs of colitis or pulmonary fibrosis.
In a Japanese man with Hermansky-Pudlak syndrome (HPS1; 203300), who had oculocutaneous albinism and a bleeding diathesis, Horikawa et al. (2000) identified compound heterozygous mutations in the HPS1 gene: a frameshift mutation (962_963insG) at codon 321 in exon 11, and a 5-prime splice site mutation (IVS5+5G-A; 604982.0007). The content of eumelanin in the patient's hairs was significantly reduced. Histologic analysis using light and electron microscopy revealed that melanocytes in the patient's epidermis contained giant melanosomes.
For discussion of the splice site mutation in the HPS1 gene (IVS5+5G-A) that was found in compound heterozygous state in a patient with Hermansky-Pudlak syndrome (HPS1; 203300) by Horikawa et al. (2000), see 604982.0006.
Feng, G. H., Bailin, T., Oh, J., Spritz, R. A. Mouse pale ear (ep) is homologous to human Hermansky-Pudlak syndrome and contains a rare 'AT-AC' intron. Hum. Molec. Genet. 6: 793-797, 1997. [PubMed: 9158155] [Full Text: https://doi.org/10.1093/hmg/6.5.793]
Feng, L., Novak, E. K., Hartnell, L. M., Bonifacino, J. S., Collinson, L. M., Swank, R. T. The Hermansky-Pudlak syndrome 1 (HPS1) and HPS2 genes independently contribute to the production and function of platelet dense granules, melanosomes, and lysosomes. Blood 99: 1651-1658, 2002. [PubMed: 11861280]
Fukai, K., Oh, J., Frenk, E., Almodovar, C., Spritz, R. A. Linkage disequilibrium mapping of the gene for Hermansky-Pudlak syndrome to chromosome 10q23.1-q23.3. Hum. Molec. Genet. 4: 1665-1669, 1995. [PubMed: 8541858] [Full Text: https://doi.org/10.1093/hmg/4.9.1665]
Gahl, W. A., Brantly, M., Kaiser-Kupfer, M. I., Iwata, F., Hazelwood, S., Shotelersuk, V., Duffy, L. F., Kuehl, E. M., Troendle, J., Bernardini, I. Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome). New Eng. J. Med. 338: 1258-1264, 1998. [PubMed: 9562579] [Full Text: https://doi.org/10.1056/NEJM199804303381803]
Hall, S. L., Padgett, R. A. Conserved sequences in a class of rare eukaryotic nuclear introns with non-consensus splice sites. J. Molec. Biol. 239: 357-365, 1994. [PubMed: 8201617] [Full Text: https://doi.org/10.1006/jmbi.1994.1377]
Horikawa, T., Araki, K., Fukai, K., Ueda, M., Ueda, T., Ito, S., Ichihashi, M. Heterozygous HPS1 mutations in a case of Hermansky-Pudlak syndrome with giant melanosomes. Brit. J. Derm. 143: 635-640, 2000. [PubMed: 10971344] [Full Text: https://doi.org/10.1111/j.1365-2133.2000.03725.x]
Martina, J. A., Moriyama, K., Bonifacino, J. S. BLOC-3, a protein complex containing the Hermansky-Pudlak syndrome gene products HPS1 and HPS4. J. Biol. Chem. 278: 29376-29384, 2003. [PubMed: 12756248] [Full Text: https://doi.org/10.1074/jbc.M301294200]
Oh, J., Bailin, T., Fukai, K., Feng, G. H., Ho, L., Mao, J., Frenk, E., Tamura, N., Spritz, R. A. Positional cloning of a gene for Hermansky-Pudlak syndrome, a disorder of cytoplasmic organelles. Nature Genet. 14: 300-306, 1996. [PubMed: 8896559] [Full Text: https://doi.org/10.1038/ng1196-300]
Oh, J., Ho, L., Ala-Mello, S., Amato, D., Armstrong, L., Bellucci, S., Carakushansky, G., Ellis, J. P., Fong, C.-T., Green, J. S., Heon, E., Legius, E., Levin, A. V., Nieuwenhuis, H. K., Pinckers, A., Tamura, N., Whiteford, M. L., Yamasaki, H., Spritz, R. A. Mutation analysis of patients with Hermansky-Pudlak syndrome: a frameshift hot spot in the HPS gene and apparent locus heterogeneity. Am. J. Hum. Genet. 62: 593-598, 1998. [PubMed: 9497254] [Full Text: https://doi.org/10.1086/301757]
Schallreuter, K. U., Frenk, E., Wolfe, L. S., Witkop, C. J., Wood, J. M. Hermansky-Pudlak syndrome in a Swiss population. Dermatology 187: 248-256, 1993. [PubMed: 8274781] [Full Text: https://doi.org/10.1159/000247258]
Shotelersuk, V., Hazelwood, S., Larson, D., Iwata, F., Kaiser-Kupfer, M. I., Kuehl, E., Bernardini, I., Gahl, W. A. Three new mutations in a gene causing Hermansky-Pudlak syndrome: clinical correlations. Molec. Genet. Metab. 64: 99-107, 1998. [PubMed: 9705234] [Full Text: https://doi.org/10.1006/mgme.1998.2679]
Wildenberg, S. C., Fryer, J. P., Gardner, J. M., Oetting, W. S., Brilliant, M. H., King, R. A. Identification of a novel transcript produced by the gene responsible for the Hermansky-Pudlak syndrome in Puerto Rico. J. Invest. Derm. 110: 777-781, 1998. [PubMed: 9579545] [Full Text: https://doi.org/10.1046/j.1523-1747.1998.00183.x]
Wildenberg, S. C., Oetting, W. S., Almodovar, C., Krumwiede, M., White, J. G., King, R. A. A gene causing Hermansky-Pudlak syndrome in a Puerto Rican population maps to chromosome 10q2. Am. J. Hum. Genet. 57: 755-765, 1995. [PubMed: 7573033]