The disease HPS-1 represents the subset of HPS caused by mutations in the gene HPS  or HPS1. The number of patients is large because approximately 400 individuals in northwest Puerto Rico have HPS-1 as a result of a founder effect in this genetic isolate [10,11]. All the northwest Puerto Rican patients have their disease due to homozygosity for a 16-bp duplication in exon 15 of HPS1 [1,7,13]. Among non-Puerto Rican patients with HPS, only 25–40% have demonstrable mutations in HPS1 [1,5]; in general, these individuals appear phenotypically indistinguishable from patients who do not have HPS-1. The murine counterpart of HPS-1 is pale ear [35,36].
The HPS1 gene and its mutations
In 1995, the first HPS-causing gene was mapped to chromosome 10q23.1–23.3 by linkage disequilibrium using families from northwest Puerto Rico and a Swiss genetic isolate [37,38]. Cloning of the gene's cDNA (GenBank accession #U65676) revealed an open reading frame of 2100 bp  and the genomic structure of HPS1 was subsequently reported . HPS1 consists of 20 exons spanning approximately 30.5 kb, with an intron 16 which is a member of the rare U12-type ‘AT-AC’ class of introns [36,39]. Recently, a pseudogene of HPS1 containing several intact exons, including exons 3, 4, and 6, was localized to chromosome 22q12.2–12.3 .
The human HPS1 gene has a standard transcript of 3.0 kb and is expressed in most tissues . Minor 3.9- and 4.4-kb mRNAs are apparent on northern blot analysis. A 1.5-kb transcript with the same 5′ sequence as the published cDNA but with a different 3′ sequence is present in bone marrow and melanoma cells . Four alternative splices of HPS1 have also been described [7,39].
The original report of the isolation of HPS1 described the 16-bp duplication in exon 15 found among northwest Puerto Rican patients . This frameshift mutation produces no mRNA , presumably due to ‘nonsense-mediated decay’ [42,43] and has not been reported in any patient from outside of northwest Puerto Rico [1,5]. The duplication is easily detected using PCR amplification of a portion of exon 15 .
Other mutations initially reported include T322insC, found in a Swiss isolate and in Irish patients, and A441insA, found in a Japanese patient . The T322insC mutation was subsequently reported in families of Italian/German/Ukrainian, Swiss, Irish/German, French, and Scottish heritage [5,7,44]. Haplotype analysis indicates that it arose at least twice in northern Europe . A T322delC mutation has been found in German and Japanese families [5,44] and S396delC has appeared in Ukrainian, Dutch/German, and Irish/English/French/Norwegian patients [5,44]. The region of codons 321–324 appears to be a mutation hot spot  and codon 396 may be another area subject to recurrent mutation [5,44]. In all, 12 different mutations, including deletions, insertions, nonsense mutations, and splice junction mutations have been reported [1,6,45]. The mutations E133X, T322delC, and S396del have been shown to produce decreased or undetectable mRNA on northern blot analysis .
Except for the single codon deletion 55Ile , all the HPS1 gene mutations reported to date, as well as the frameshift mutations of the pale ear mouse [35,36], are predicted to result in a truncated protein. This suggests that the carboxy terminal portion of the HPS1 protein is critical for function. Furthermore, no missense mutation in HPS1 has been reported, perhaps because single base changes in HPS1 are not pathologic and constitute polymorphisms instead. At least 23 nonpathologic DNA sequence polymorphisms have been reported [39,44,45], including four which result in amino acid substitutions (G283W, P491R, R603Q, and V630I). Recently, a V4A substitution was found to also be an HPS1 polymorphism .
The HPS1 protein and its cell biology
The protein HPS1 consists of 700 amino acids and has a predicted molecular weight of 79.3 kDa . Although it has two potential N-glycosylation sites at residues 528 and 560, HPS1 does not appear to be glycosylated . The protein has no general homology to proteins with a known function but it does contain the sequence DKF(L/V)KNRG, which resembles the Chediak–Higashi syndrome (CHS) protein [7,48] (see below). In addition, the carboxy terminus of HPS1 contains a putative melanosomal localization signal, PLL, that is present in other melanosomal proteins . The HPS1 amino acid sequence is 81% conserved between human and mouse , with similar conservation between human and rat . A predicted Drosophila protein of unknown function has high sequence identity to the carboxy terminal portion of HPS1 (GenBank accession #AAF58194) but no homologues can be found in bacteria, yeast, worm or plants.
HPS1 also contains a His-Leu-Leu sequence near the carboxy terminus. This recognition marker could serve as a sorting signal to target the protein to late endosomal/lysosomal compartments [50,51], which might include the melanosomes and dense granules of specialized cells . Localization studies indicate that HPS1 is not associated with lysosomes , consistent with the mild and indirect lysosomal defects observed in HPS-1 patients’ cells .
HPS1 has also been described as a component of two distinct high molecular weight complexes . In non-melanotic cells such as fibroblasts, HPS1 forms a complex of approximately 200 kDa which is widely distributed through the cytosol. In melanotic cells, HPS1 is partitioned between the cytosolic 200-kDa complex and a complex of greater than 500 kDa that appears to consist of the 200-kDa complex in transient association with membranous components. The large complex, located in the perinuclear region, is associated with tubulovesicular structures, small non-coated vesicles, and nascent and early-stage melanosomes but not with later stage melanosomes. These findings suggest that the HPS1 protein complex is involved in the biogenesis of early melanosomes . Other localization studies indicate that HPS1 is present in the perinuclear region of normal melanocytes and may be associated with a cisternal network outside of the Golgi zone . This would place HPS1 in association with premelanosomes as they form from the smooth endoplasmic reticulum. A fine granular staining pattern throughout the cytosol and dendrites was also observed for HPS1, supporting a melanosomal localization.
This hypothesis is bolstered by studies of the pigment-forming proteins tyrosinase related protein-1 (TRP-1) and granulophysin in melanocytes cultured from HPS-1 patients. A large granular pattern of expression appeared for these proteins throughout the cells, consistent with the large membrane complexes observed ultrastructurally . Consequently, it was proposed that the HPS1 gene product regulates, in part, the trafficking of melanocyte-specific proteins from the trans-Golgi network (TGN) to preformed premelanosomes .
In our experience, the low abundance of HPS1 in fibroblasts has prevented definitive determination of its subcellular localization. In these cells, the protein does not appear essential, since fibroblasts from HPS-1 patients appear to thrive. In fact, such fibroblasts display normal distribution and trafficking of the lysosomal membrane proteins, CD63 and LAMP-1, in contrast to cells from patients with ADTB3A mutations, which show increased routing of these lysosomal proteins through the plasma membrane . It has been shown, however, that HPS1 does not functionally interact with AP3 .