10q24.2. View the map and BAC clones of FISH (data from UCSC genome browser).
Isoform a (NM_000195): 20 exons, 30,750bp, chr10:99,840,542-99,871,291.
Isoform b (NM_182637): 19 exons, 30,750 bp, chr10:99,840,542-99,871,291.
Isoform c (NM_182939): 10 exons, 17,801 bp, chr10:99,853,491-99,871,291.
Isoform d (NM_182638): 17 exons, 30,750 bp, chr10:99,840,542-99,871,291.
1) NM_182637 uses an alternative splicing donor of exon 6 by extending 43bp to intron 6, which results in a frameshift and a stop codon on 195. The resulting 194aa protein (isoform b) has a distinct C-terminus and is shorter than isoform (a) which is predicted as non-functional due to permanently suppression as a nonsense-mediated mRNA decay (NMD) candidate.
2) NM_182639 skips the splicing donor of intron 10 and uses an alternate 3' coding region compared to NM_000195. It encodes isoform (c), which has a shorter and distinct C-terminus compared to isoform (a).
3) NM_182638 skips exons 5, 7 and 9 in the coding region compared to NM_000195. It encodes the shorter isoform (d), which is permanently suppressed because it is a nonsense-mediated mRNA decay (NMD) candidate.
The figure shows the comparison of these four isoforms (data from UCSC genome browser).
Search the 5'UTR and 1kb upstream regions (seq1=human HPS1, seq2=mouse Hps1) by CONREAL with 80% Position Weight Matrices (PWMs) threshold (view results here).
a) Transcript variant 1 (NM_000195), 3,714bp, view ORF and the alignment to genomic. Note that intron 16 contains a rare "AT-AC" nonconsensus splice site.
b) Transcript variant 2 (NM_182637), 3,667bp, view ORF and the alignment to genomic. Note that intron 15 contains a rare "AT-AC" nonconsensus splice site.
c) Transcript variant 3 (NM_182639), 1,625bp, view ORF and the alignment to genomic.
d) Transcript variant 4 (NM_182638), 3,320bp, view ORF and the alignment to genomic. Note that intron 13 contains a rare "AT-AC" nonconsensus splice site.
Tissue specificity: ubiquitous. On Northern blot analysis, the standard transcript is 3.0kb. Minor 3.9kb and 4.4kb mRNAs are apparent (Oh, et al (1996)). An additional 1.5kb transcript (variant 3) was found in bone marrow and melanoma cells (Wildenberg et al).
BMR: Bone marrow; SPL: Spleen; TMS: Thymus; BRN: Brain; SPC: Spinal cord; HRT: Heart; MSL: Skeletal muscle; LVR; Liver; PNC: Pancreas; PST: Prostate; KDN: Kidney; LNG: Lung. (data from GeneCards )
Isoform a ( NP_000186): 700aa, ExPaSy NiceProt view of Swiss-Prot:Q92902.
Isoform b ( NP_872575): 194aa.
Isoform c ( NP_872577): 324aa.
Isoform d ( NP_872576): 195aa.
Synonym: Hermansky-Pudlak syndrome 1 protein.
|Protein||NP_062297 (704aa)||NP_414541 (706aa)||0146520 (713aa)||NP_610997 (596aa)||XP_309433 (602aa)|
View multiple sequence alignment (PDF file) by ClustalW and GeneDoc.
(1) Domains predicted by SMART(isoform a):
a) coiled coil: 31-47
b) low complexity: 229-244
c) low complexity: 275-286
(2) Transmembrane domains predicted by SOSHI(isoform a): none.
(3) Graphic view of InterPro domain structure.
(1) Predicted results by ScanProsite (isoform a):
a) N-glycosylation site [pattern] [Warning: pattern with a high probability of occurrence]:
528 - 531 NITM, 560 - 563 NCSQ.
b) Protein kinase C phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
25 - 27 SlR, 228 - 230 SlR, 258 - 260 SpR, 418 - 420, SlR, 525 - 527 SrR, 562 - 564 SqK.
c) N-myristoylation site [pattern] [Warning: pattern with a high probability of occurrence]:
31 - 36 GqseNE, 202 - 207 GgeeAL, 283 - 288 GgssAE, 639 - 644 GMlgGD.
(2) Predicted results of subprograms by PSORT II(isoform a):
a) N-terminal signal peptide: none
b) KDEL ER retention motif in the C-terminus: none
c) ER Membrane Retention Signals: none
d) VAC possible vacuolar targeting motif: none
e) Actinin-type actin-binding motif: type 1: none; type 2: none
f) Prenylation motif: none
g) memYQRL transport motif from cell surface to Golgi: none
h) Tyrosines in the tail: none
i) Dileucine motif in the tail: none
(1) ModBase: none.
(2) 3D models of isoform (a) predicted by SPARKS (fold recognition) below. View the models by PDB2MGIF.
This protein does not exist in the current release of SWISS-2DPAGE.
Computed theoretical MW=79,320Da, pI=5.68 (Q92902, isoform a).
Computed theoretical MW=22,153Da, pI=4.66 (isoform b).
Computed theoretical MW=36,476Da, pI=4.74 (isoform c).
Computed theoretical MW=21,196Da, pI=6.14 (isoform d).
a) Biological process: lysosome organization and biogenesis.
b) Component of multiple cytoplasmic organelles.
c) Maturation or structure of cytoplasmic organelles, i.e. melanosomes, platelet dense bodies, lysosomes. Likely involved in assembly of these organelles.
d) Involved in the biogenesis of early melanosomes and the sorting of tyrosinase and Tyrp1 (view diagram of melanosome maturation and melanosomal protein sorting here).
Cytoplasm, may be associated with membrane fraction.
The HPS1 protein (HPS1p) was ariginally predicted to be an integral membrane protein having two transmembrane domains (residues 79-95 and 369-396). However, subsequent biochemical characterization using specific antibodies revealed that endogenous HPS1p from human and mouse cells exists as both cytosolic and peripheral membrane proteins. Immunoelectron microscopy analyses of HPS1p in melanoma-derived cell lines or non-melanogenic cell lines have shown that the protein is associated with the trans-Golgi network (Starcevic, et al). Membranous complexes of HPS-1 melanocytes are macroautophagosomal representatives of the lysosomal compartment (Smith, et al).
HPS1 is a component of a protein complex termed biogenesis of lysosome-related organelles complex 3 (BLOC-3), where HPS4 is residing as another subunit (Chiang, et al; Martina, et al; Nazarian, et al). The BLOC-3 complex is a moderately asymmetric complex with a molecular mass of about 175 kD (view diagram of BLOC-3 complex here). The BLOC-3 complex dissociates into smaller complex upon Tris treatment and a portion of HPS1 exists in a cytosolic complex that does not contain HPS4 (Chiang, et al). Two regions in HPS1, spanning amino acids 1-249 and 506-700 are required for binding to HPS4 (residues 340-528)(Carmona-Rivera, et al (2013)). Interaction of BLOC-3 with the GTP-bound form of Rab9 is mediated by HPS4 and the switch I and II regions of Rab9, suggesting that BLOC-3 might function as a Rab9 effector in the biogenesis of LROs (Kloer, et al). BLOC-3 is a Rab32 and Rab38 guanine nucleotide exchange factor (GEF), to promote specific membrane recruitment of Rab32/38 (Gerondopoulos, et al).
View interactions in HPRD
View co-occured partners in literature searched by PPI Finder.
HPS1 may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. The mechanism is distinct from that dependent on the AP-3 complex (Dell'Angelica, et al, Feng, et al). HPS4 and HPS1 proteins may function in the same pathway of organelle biogenesis (Suzuki, et al (2002)) (view diagram of BLOC-3 pathway here). In mutant cells lacking BLOC-3, the percentages of cells displaying pronounced perinuclear accumulation were reduced (Nazarian, et al; Falcon-Perez, et al). A relatively lower frequency of microtubule-dependent movement events, either toward or away from the perinuclear region were observed in BLOC-3 deficient cells. This suggests that BLOC-3 is required for optimal attachment of late endosomes to microtubule-dependent motors (Falcon-Perez, et al). BLOC-3 defines a novel Rab GEF family with a specific function in the biogenesis of lysosome-related organelles (Gerondopoulos, et al).
30 alleles to date.
|Germany||Sandrock, et al|
|I55delATC||in-frame||Afghan||Oh, et al (1998)|
|Exon 5||288delG||288delG||G96delT||frame-shift |
|Japanese||Spritz, et al|
|Exon 5||355delC||355delC||H119delC||frame-shift |
|Hermos, et al|
|Exon 5||391C>T||391C>T||R131X||nonsense||Spanish |
|Hermos, et al;|
Wei, et al (2011)
|Shotelersuk, et al|
|Intron 5||splicing donor |
|Oh, et al (1998);|
Suzuki, et al (2004);
Vincent, et al
|Exon 6||418delG||418delG||A140delG||frame-shift |
|Hermos, et al|
|Exon 6||467_476del||467_476del||Y156del 10bp||frame-shift |
|Carmona-Rivera, et al (2011a)|
|Exon 6||507G>A||507G>A||E169ins 43bp||splicing |
|African American||Merideth, et al|
|Intron 6||splicing donor|
|507+1G>A||E169ins 43bp||splicing |
|Japanese||Natsuga, et al|
|Exon 7||532insC||532insC||Q178insC||frame-shift |
|Japanese||Ito, et al;|
Iwakawa, et al
|Hermos, et al|
|Exon 10||937G>A||937G>A||G313S||missense |
|Perto Rican||Carmona-Rivera, et al (2011b)|
|Ukrainian||Oh, et al (1998)|
|Japanese ||Hermos, et al|
|Oh, et al (1998)|
Merideth, et al
|Oh, et al (1998)|
Wei, et al (2010)
Wei, et al (2011)
|Mexican||Carmona-Rivera, et al (2011a)|
|Intron 11||splicing acceptor |
|I330del 168bp||splicing |
|Indian||Vincent, et al|
|Caucasian||Oh, et al (1998)|
|Japanese||Oh, et al (1996)|
|Hermos, et al|
|Exon 15||1471_1487dup||1471_1487dup||P496ins 16bp||frame-shift|
|Puerto Rican||Oh, et al (1996)|
|Japanese||Ito, et al|
|Intron 17||splicing acceptor |
|?||?||splicing||Caucasian||Oetting, et al|
|Exon 18||1749G>A||1749G>A||W583X||nonsense||Japanese||Ito, et al|
|Chinese||Wei, et al (2011)|
|Chinese||Wei, et al (2009)|
|Exon 20||1996G>T||1996G>T||E666X||nonsense||Scottish||Oh, et al (1998)|
|Exon 20||2003T>C||2003T>C||L668P||missense||Japanese||Ito, et al|
(Numbering of genomic and cDNA sequence is based on the start codon of RefSeq NM_000195. View ORF here.)
The most common mutation is the 16bp duplication within exon 15 (founder mutation) in northwest Puerto Rican patients. In Japanese, the IVS5 +5G>A mutation appears to represent a founder effect (Ito, et al). A frameshift hot spot at codons 321-322 is apparent in non-Puerto Rican patients (Oh, et al (1998)). Exons 5, 11, and 15 are apparently hotspots for mutation screening.
Note that a pseudogene has been detected on chromosome 22q12.2-12.3 which has high sequence similarity to HPS1 exons 2-5 and 100% sequence homology to HPS1 exon 6. Careful check should be alerted when base pair change is observed in these regions.
Most of the HPS1 gene mutations are frameshift mutations or nonsense mutations that disrupt the function of the HPS1 protein. Five splicing mutations have been reported including the c.507G>A mutation. Two missense mutations (L239P and L668P) have been reported. L239 residue is conserved in different species (refer to the multiple sequence alignment PDF file). Overexpression of L668P mutant HPS1 protein in le-melanocytes did not restore the stability of endogeneous HPS4, a subunit of BLOC-3 (Ito, et al).
Interestingly, both the silence mutation (c.507G>A) and the splicing mutation (c.507+1G>A) lead to the activation of a cryptic splice site at +43 bp within intron 6 of the HPS1 gene, which results in a frameshift of the mutant transcript, predicting that it will be targeted for nonsense-mediated decay or that it will produce a truncated protein with a premature stop codon 25 amino acids downstream of E169E (Merideth, et al; Netsuga, et al), which is the same as isoform (b).
The c.1932delC mutation leads to a longer HPS1 protein that a novel 79-residue peptide replaces the wild-type 56-residue peptide after the mutation site at D644 (Wei, et al (2009)). However, the elongated HPS1 protein is unstable in the patient's platelets (Wei and Li.).
Hermansky-Pudlak syndrome (HPS, OMIM 203300) was first described by Hermansky and Pudlak (1959). It is a rare autosomal recessive disorder in which oculocutaneous albinism, bleeding tendency, and lysosomal ceroid storage result from defects of multiple cytoplasmic organelles: melanosomes, platelet-dense granules, and lysosomes. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 1 (HPS-1, OMIM 604982). HPS-1 is the most common HPS type.
Some HPS-1 adult patients developed pulmonary fibrosis and granulomatous colitis (Hermos et al). These complications are common among Puerto Rican HPS-1 patients but have not appeared in HPS-2 or HPS-3 patients. Oh et al (1996) found that the different clinical HPS phenotypes were associated with different HPS1 frameshifts, which suggested that differentially truncated HPS1 polypeptides may have somewhat different consequences for subcellular function. In some HPS1 patients, no apparent bleeding tendency were noticed, suggesting the severity of HPS1 is associated with the genotype (Wei, et al (2009, 2010)).