Alternative titles; symbols
HGNC Approved Gene Symbol: HPS4
Cytogenetic location: 22q12.1 Genomic coordinates (GRCh38) : 22:26,443,109-26,483,863 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q12.1 | Hermansky-Pudlak syndrome 4 | 614073 | Autosomal recessive | 3 |
In the mouse, more than 15 loci manifest mutant phenotypes similar to human Hermansky-Pudlak syndrome (203300), including 'pale ear' (ep), the mouse homolog of HPS1 (604982), which is mutant in one form of Hermansky-Pudlak syndrome. Mouse ep has a phenotype identical to that of another mutant, 'light ear' (le) (Lane and Green, 1967), which suggested that the human homolog of le is a possible human HPS locus. Suzuki et al. (2002) identified the human le homolog, HPS4, and found mutations in that gene in a number of non-Puerto Rican individuals with HPS. 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 colocalize in vesicles of the cell body. In addition, the HPS1 protein is absent in tissues of le mutant mice. These results suggested that the HPS4 and HPS1 proteins function in the same pathway of organelle biogenesis. Suzuki et al. (2002) found that the full-length human HPS4 cDNA encodes a polypeptide of 708 amino acids with an apparent molecular weight of 76.9 kD.
Anderson et al. (2003) found that the HPS4 gene produces at least 2 alternatively spliced mRNA transcripts that differ at their 5-prime ends.
Martina et al. (2003) determined that HPS1 and HPS4 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.
Suzuki et al. (2002) found that the HPS4 gene contains 13 exons.
The mouse le locus had been mapped to chromosome 5. Suzuki et al. (2002) subjected BACs spanning the le region to exon-trapping and compared sequences with genomic and expressed sequence tag (EST) databases. With availability of the complete DNA sequence of human chromosome 22, it was shown that the organization of the le region of mouse chromosome 5 and human 22q11.2-q12.2 is essentially identical.
Gross (2014) mapped the HPS4 gene to chromosome 22q12.1 based on an alignment of the HPS4 sequence (GenBank BC065030) with the genomic sequence (GRCh38).
Suzuki et al. (2002) demonstrated that the le mouse has a gln50-to-ter (Q50X, CAG-TAG) nonsense mutation in the Hps4 protein. In 7 European patients with Hermansky-Pudlak syndrome-4 (HPS4; 614073), Suzuki et al. (2002) identified 5 different causative mutations in the HPS4 gene (606682.0001-606682.0005).
In 22 patients with HPS who were negative for mutation in 3 HPS-associated genes, Anderson et al. (2003) screened for mutations in the HPS4 gene by SSCP analysis and/or direct sequencing and identified homozygous or compound heterozygous mutations, including the previously reported frameshift insertion (606682.0002) in 2 patients, as well as 3 nonsense mutations (606682.0006-606682.0008) and a missense mutation (H154R; 606682.0010).
Bachli et al. (2004) reported a patient from Sri Lanka who had oculocutaneous albinism and severe pulmonary fibrosis without granulomatous colitis in whom they identified a novel frameshift mutation (606682.0009) in the HPS4 gene.
In a patient with Hermansky-Pudlak syndrome (HPS4; 614073) from Germany (South Tyrol), Suzuki et al. (2002) found homozygosity for a gln631-to-ter (Q631X; CAG-TAG) nonsense mutation in the HPS4 gene.
In a German patient with Hermansky-Pudlak syndrome (HPS4; 614073), Suzuki et al. (2002) found homozygosity for a 5-bp (AAGCA) insertion at codon gln698 of the HPS4 gene, causing a frameshift.
In a 61-year-old Hungarian man (patient 95) with HPS, Anderson et al. (2003) identified homozygosity for the AAGCA insertion in the HPS4 gene. In addition, they detected heterozygosity for the variant in a 3-year-old boy (patient 27) of mixed European ancestry with HPS. The authors were unable to find a second mutation in the latter patient in the coding region or intron/exon boundaries of HPS4, and suggested that he might have an intronic mutation or a mutation in the promoter region.
In a patient from northern Europe with Hermansky-Pudlak syndrome (HPS4; 614073), Suzuki et al. (2002) found a 1-bp deletion (T) from codon phe19 of the HPS4 gene, causing a frameshift. The deletion was present in heterozygous state; no mutation in the second allele was found, most likely reflecting either incomplete sensitivity of the SSCP/heteroduplex mutation screening method, or the occurrence of the mutation in the promoter or intervening sequences beyond the regions subjected to mutation screening.
In patients with Hermansky-Pudlak syndrome (HPS4; 614073) from 3 presumably unrelated families, one of them consanguineous, in southern Italy, Suzuki et al. (2002) found a gln181-to-ter (Q181X, CAG-TAG) nonsense mutation in the HPS4 gene in homozygous state.
In a Dutch family, Suzuki et al. (2002) found that multiple members with Hermansky-Pudlak syndrome (HPS4; 614073) were heterozygous for a 24-bp tandem duplication of the HPS4 gene. Amino acids ala316 through glu323 were duplicated. No mutation in the second allele was found, most likely reflecting either incomplete sensitivity of the SSCP/heteroduplex mutation screening method, or the occurrence of a mutation in the promoter or intervening sequences beyond the regions subjected to mutation screening.
In a 61-year-old Hungarian man (patient 95) with Hermansky-Pudlak syndrome (HPS4; 614073), Anderson et al. (2003) identified homozygosity for an 837C-T transition in exon 8 of the HPS4 gene, resulting in an arg217-to-ter (R217X) substitution. The R217X variant was also identified in 2 brothers with HPS who were of English and Polish origin (patients 30 and 38) and carried the mutation in compound heterozygosity with a 694A-G transition in exon 8, resulting in a his154-to-arg (H154R; 606682.0010) substitution.
In 2 Indian sisters (patients 36 and 37) with Hermansky-Pudlak syndrome (HPS4; 614073), Anderson et al. (2003) identified compound heterozygosity for 2 nonsense mutations in the HPS4 gene: a 600G-T transversion in exon 6, resulting in a glu138-to-ter (E138X) substitution, and an 852G-T transversion in exon 8, resulting in a glu222-to-ter (E222X; 606682.0008).
For discussion of the 852G-T transversion in exon 8 of the HPS4 gene, resulting in a glu222-to-ter (E222X) substitution, that was found in compound heterozygous state in 2 Indian sisters with Hermansky-Pudlak syndrome (HPS4; 614073) by Anderson et al. (2003), see 606682.0007.
In a Sri Lankan patient with Hermansky-Pudlak syndrome (HPS4; 614073), Bachli et al. (2004) identified homozygosity for a 1-bp deletion (C) at codon 685 (P685delC) of the HPS4 gene, resulting in a frameshift and an early termination codon approximately 21 bp upstream of the normal stop site.
For discussion of the 649A-G transition in exon 6 of the HPS4 gene, resulting in a his154-to-arg (H154R) substitution, that was found in compound heterozygous state in 2 brothers with Hermansky-Pudlak syndrome (HPS4; 614073) by Anderson et al. (2003), see 606682.0006.
Anderson, P. D., Huizing, M., Claassen, D. A., White, J., Gahl, W. A. Hermansky-Pudlak syndrome type 4 (HPS-4): clinical and molecular characteristics. Hum. Genet. 113: 10-17, 2003. [PubMed: 12664304] [Full Text: https://doi.org/10.1007/s00439-003-0933-5]
Bachli, E. B., Brack, T., Eppler, E., Stallmach, T., Trueb, R. M., Huizing, M., Gahl, W. A. Hermansky-Pudlak syndrome type 4 in a patient from Sri Lanka with pulmonary fibrosis. Am. J. Med. Genet. 127A: 201-207, 2004. [PubMed: 15108212] [Full Text: https://doi.org/10.1002/ajmg.a.20683]
Gross, M. B. Personal Communication. Baltimore, Md. 11/26/2014.
Lane, P. W., Green, E. L. Pale ear and light ear in the house mouse: mimic mutations in linkage groups XII and XVII. J. Hered. 58: 17-20, 1967. [PubMed: 6031677] [Full Text: https://doi.org/10.1093/oxfordjournals.jhered.a107529]
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]
Suzuki, T., Li, W., Zhang, Q., Karim, A., Novak, E. K., Sviderskaya, E. V., Hill, S. P., Bennett, D. C., Levin, A. V., Nieuwenhuis, H. K., Fong, C.-T., Castellan, C., Miterski, B., Swank, R. T., Spritz, R. A. Hermansky-Pudlak syndrome is caused by mutations in HPS4, the human homolog of the mouse light-ear gene. Nature Genet. 30: 321-324, 2002. [PubMed: 11836498] [Full Text: https://doi.org/10.1038/ng835]