Alternative titles; symbols
HGNC Approved Gene Symbol: HPS3
Cytogenetic location: 3q24 Genomic coordinates (GRCh38) : 3:149,129,638-149,173,732 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q24 | Hermansky-Pudlak syndrome 3 | 614072 | Autosomal recessive | 3 |
By use of homozygosity mapping on pooled DNA of 6 families with Hermansky-Pudlak syndrome (HPS3; 614072) from central Puerto Rico, Anikster et al. (2001) localized an HPS susceptibility locus to a 1.6-cM interval on chromosome 3q24, flanked by markers D3S3626 and D3S3705. Within this region they identified a novel gene, designated HPS3, predicted to encode a deduced 1,004-amino acid protein with a molecular mass of 113.7 kD and a pI of 6.01. The HPS3 protein contains a potential clathrin-binding motif at residues 172 to 176, 2 consensus dileucine signals, and 12 tyrosine-based sorting signals for targeting to vesicles of lysosomal lineage. Northern blot analysis demonstrated a 4.4-kb message in all tissues tested, including heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas. Expression was greatest in kidney, with strong bands in liver and placenta. While expression was also detected in normal fibroblasts, no expression was observed in fibroblasts from HPS patients from central Puerto Rico.
By positional cloning, Anikster et al. (2001) identified the HPS3 gene within the critical region of an HPS susceptibility locus on chromosome 3q24. The mouse coa gene, the homolog of HPS3, maps to chromosome 3 in a region of conserved synteny with human 3q24 (Suzuki et al., 2001).
Anikster et al. (2001) determined that the HPS3 gene contains 17 exons and spans 3,921 basepairs.
In 6 families from central Puerto Rico, Anikster et al. (2001) identified a 3,904-bp deletion in the HPS3 gene (606118.0001). The authors estimated that the deletion occurred in central Puerto Rico between 1880 and 1890. At that time, the ancestors of 3 of the HPS3 families emigrated from the town of Ciales to the towns of Aibonito, Barranquitas, and Naranjito because of harsh economic conditions in Ciales. Each of 3 the families traced its ancestry to 1 individual.
Huizing et al. (2001) identified the clinical and molecular characteristics of 8 patients with HPS3 who were of non-Puerto Rican ancestry. Five were Ashkenazi Jews; 3 of these were homozygous for a 1303+1G-A splice site mutation that caused skipping of exon 5 (606118.0002). The other 2 Ashkenazi Jews were compound heterozygotes for the 1303+1G-A mutation and either an 1831+2T-G (606118.0003) or a 2621-2A-G splicing mutation (606118.0004). A 7-year-old boy of German/Swiss extraction was compound heterozygous for a 2729+1G-C mutation (606118.0005), causing skipping of exon 14, and an arg396-to-trp missense mutation (606118.0006), with decreased mRNA production. A 15-year-old Irish/English boy was heterozygous for an 89-bp insertion between exons 16 and 17 resulting from abnormal splicing (606118.0007). A 12-year-old girl of Puerto Rican and Italian background had the 3904-bp founder deletion from central Puerto Rico (606118.0001) on 1 allele. All 8 patients had mild symptoms of HPS; indeed, 2 Jewish patients had received the diagnosis of ocular, rather than oculocutaneous, albinism.
Suzuki et al. (2001) identified the gene mutated in the 'cocoa' (coa) mouse, which is associated with an HPS-like mutant phenotype, and determined that it is homologous to the human HPS3 gene. The lack of Hps3 in the coa mice resulted in little visible pigment and reduced melanin content. Using light and electron microscopy of coa mutant melanocytes, Suzuki et al. (2001) observed small, aberrant, early melanosomes. They concluded that the normal HPS3 gene product is involved in early stages of melanosome biogenesis and maturation.
In 13 individuals with Hermansky-Pudlak syndrome (HPS3; 614072) from 6 families in central Puerto Rico, Anikster et al. (2001) identified homozygosity for a large deletion in the HPS3 gene. The deletion consists of a 3,904-bp region encompassing all of exon 1, roughly 673 bases of intron 1 and approximately 2,874 bases upstream of exon 1. The deletion breakpoint occurs within a 17-bp region shared by the Alu repeats AluYa5 and AluSg.
Huizing et al. (2001) found this mutation on one HPS3 allele of a girl of Puerto Rican and Italian ancestry; no mutation was identified on the other allele.
Huizing et al. (2001) found that 5 of 8 patients with Hermansky-Pudlak syndrome (HPS3; 614072) of non-Puerto Rican ancestry who had HPS3 were Ashkenazi Jews. Three of these were found to be homozygous for a 1303+1G-A splice mutation. A fourth was compound heterozygous for this mutation and an 1831+2T-G splice mutation (606118.0003), and a fifth was compound heterozygous for 1303+1G-A with 2621-2A-G (606118.0004). The last patient was of mixed Ashkenazi and Irish-German ancestry.
For discussion of the splice site mutation in the HPS3 gene (1831+2T-G) that was found in compound heterozygous state in patients with Hermansky-Pudlak syndrome (HPS3; 614072) by Huizing et al. (2001), see 606118.0002.
For discussion of the splice site mutation in the HPS3 gene (2621-2A-G) that was found in compound heterozygous state in patients with Hermansky-Pudlak syndrome (HPS3; 614072) by Huizing et al. (2001), see 606118.0002.
In a patient of German/Swiss ancestry with Hermansky-Pudlak syndrome (HPS3; 614072), Huizing et al. (2001) found compound heterozygosity for a splice site mutation in the HPS3 gene, 2729+1G-C, resulting in skipping of exon 14, and a missense mutation, arg396-to-trp (R396W; 606118.0006).
Huizing et al. (2001) found a C-to-T transition at nucleotide 1329 of the HPS3 gene, which resulted in an arg396-to-trp (R396W) amino acid substitution, in compound heterozygosity with 2729+1G-C (606118.0005) in a patient with Hermansky-Pudlak syndrome (HPS3; 614072).
In a 15-year-old Hermansky-Pudlak syndrome (HPS3; 614072) patient of Irish/English ancestry, Huizing et al. (2001) found an 89-bp insertion between exons 16 and 17 of the HPS3 gene. The insertion appeared to be part of intron 16 (nucleotides 44102-44191); sequencing of intron 16 revealed a heterozygous G-to-A mutation at nucleotide 44101, which introduced a new splice site. No mutation in the HPS3 gene was found on the other allele of this patient.
Anikster, Y., Huizing, M., White, J., Shevchenko, Y. O., Fitzpatrick, D. L., Touchman, J. W., Compton, J. G., Bale, S. J., Swank, R. T., Gahl, W. A., Toro, J. R. Mutation of a new gene causes a unique form of Hermansky-Pudlak syndrome in a genetic isolate of central Puerto Rico. Nature Genet. 28: 376-380, 2001. [PubMed: 11455388] [Full Text: https://doi.org/10.1038/ng576]
Huizing, M., Anikster, Y., Fitzpatrick, D. L., Jeong, A. B., D'Souza, M., Rausche, M., Toro, J. R., Kaiser-Kupfer, M. I., White, J. G., Gahl, W. A. Hermansky-Pudlak syndrome type 3 in Ashkenazi Jews and other non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiency. Am. J. Hum. Genet. 69: 1022-1032, 2001. [PubMed: 11590544] [Full Text: https://doi.org/10.1086/324168]
Suzuki, T., Li, W., Zhang, Q., Novak, E. K., Sviderskaya, E. V., Wilson, A., Bennett, D. C., Roe, B. A., Swank, R. T., Spritz, R. A. The gene mutated in cocoa mice, carrying a defect of organelle biogenesis, is a homologue of the human Hermansky-Pudlak syndrome-3 gene. Genomics 78: 30-37, 2001. [PubMed: 11707070] [Full Text: https://doi.org/10.1006/geno.2001.6644]