Alternative titles; symbols
HGNC Approved Gene Symbol: HPS5
Cytogenetic location: 11p15.1 Genomic coordinates (GRCh38): 11:18,278,670-18,322,174 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.1 | Hermansky-Pudlak syndrome 5 | 614074 | Autosomal recessive | 3 |
By screening clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1999) identified HPS5 as KIAA1017. RT-PCR followed by ELISA detected ubiquitous expression, with highest levels in liver, testis, spinal cord, and thalamus.
Using a conserved cytoplasmic domain of alpha-3 integrin (605025) in a yeast 2-hybrid screen, Wixler et al. (1999) cloned HPS5, which they designated clone 63, from a placenta cDNA library. The predicted partial HPS5 sequence contains numerous putative phosphorylation sites for protein kinase A (see 176911), protein kinase C (see 176960), and casein kinase II (see 115442), as well as a putative myristoylation site. HPS5 bound all alpha-integrin chains that had an aromatic amino acid before the first lysine of the conserved KXGFFKR motif, including alpha-2 (192974), alpha-3, alpha-3B, alpha-5 (135620), and alpha-6A.
In mice there are at least 16 naturally occurring hypopigmentation models of Hermansky-Pudlak syndrome (HPS; 203300), and 9 of these have been characterized at the molecular level. Zhang et al. (2003) used positional candidate and transgenic rescue approaches to identify the genes mutated in ruby-eye-2 (ru2) and ruby-eye (ru; 607522), 2 'mimic' mouse models of HPS. They determined that these genes are orthologs of the human genes mutated in individuals with HPS5 and HPS6, respectively. Both genes are found only in higher eukaryotes. The human ru2 ortholog HPS5 contains 1,129 amino acids and is 81% identical to the mouse protein. Northern blot analysis of mouse tissues detected a 4.8-kb ru2 transcript in all tissues tested, with lowest expression in skeletal muscle and spleen. Zhang et al. (2003) concluded that ru and ru2 represent a novel class of genes that evolved in higher organisms to govern the synthesis of highly specialized lysosome-related organelles.
By genomic sequence analysis, Zhang et al. (2003) determined that both the mouse ru2 gene and the human HPS5 gene have 23 exons.
By radiation hybrid analysis, Nagase et al. (1999) mapped the HPS5 gene to chromosome 11.
By genomic sequence analysis, Zhang et al. (2003) mapped the mouse ru2 gene to chromosome 7 and the human HPS5 gene to chromosome 11p15-p13.
By coimmunoprecipitation and yeast 2-hybrid analyses, Zhang et al. (2003) showed that the ru and ru2 proteins directly interact in a complex that they referred to as 'biogenesis of lysosome-related organelles complex-2,' or BLOC2.
By immunocytochemical analysis of LAMP3 (605883) localization in fibroblasts from patients with Hermansky-Pudlak syndrome-5 (HPS5; 614074) and truncating mutations in the HPS5 gene and from controls, Huizing et al. (2004) observed that normal fibroblasts showed a typical lysosomal punctate distribution of LAMP3 throughout the cell, to the very tips of the fibroblasts, whereas patient cells showed similar localization in the perinuclear area, but very minimal localization in the dendritic tips. The authors concluded that HPS5 plays a role in the movement of vesicles from the perinuclear region to the periphery of the cell.
In a 3-year-old Turkish boy with Hermansky-Pudlak syndrome-5 (HPS5; 614074), Zhang et al. (2003) identified a homozygous 4-bp deletion (607521.0001) in the HPS5 gene.
In 4 patients with HPS5, including 2 sisters, Huizing et al. (2004) identified homozygous and compound heterozygous mutations in the HPS5 gene (see e.g., 607521.0002-607521.0004).
In a 92-year-old man with HPS5, Ringeisen et al. (2013) identified homozygosity for a 1-bp deletion in the HPS5 gene (607521.0006).
In a 27-year-old Turkish man with HPS5, Stephen et al. (2017) identified homozygosity for an intronic mutation in the HPS5 gene (607521.0007).
Zhang et al. (2003) stated that ru and ru2 mice are completely indistinguishable in appearance. Although lysosomal morphology is normal in both mice, kidney proximal tubule cells secrete lysosomal enzymes into urine at greatly reduced rates in both. Platelet dense granules are very deficient in critical components such as serotonin and adenine nucleotides in both, leading to functionally abnormal platelets and prolonged bleeding times. Another subcellular organelle, the mast cell granule, undergoes unregulated 'kiss-and-run' fusion at the plasma membrane of mast cells of ru mice.
In a 3-year-old Turkish boy with Hermansky-Pudlak syndrome (HPS5; 614074), Zhang et al. (2003) identified a homozygous 4-bp deletion (AGTT) at codons leu675 to val676 in the HPS5 gene. The mutation resulted in a frameshift with truncation of the nonsense polypeptide at codon 682, causing loss of 40% of the protein at the C terminus.
In a 10-year-old boy of English, Irish, Dutch, and Swedish ancestry (patient 106) with Hermansky-Pudlak syndrome (HPS5; 614074), Huizing et al. (2004) identified compound heterozygosity for 2 mutations in the HPS5 gene: a c.2593C-T transition in exon 18, resulting in an arg865-to-ter (R865X) substitution, and a 1-bp deletion (c.2624delT; 607521.0003) in exon 18, causing a frameshift predicted to result in a premature termination codon. Northern blot analysis of mRNA isolated from patient fibroblasts showed reduced amounts of HPS5 transcripts, consistent with nonsense-mediated RNA decay.
Stephen et al. (2017) performed Western blot analysis in this patient and observed severely reduced HPS5 protein levels compared to control.
For discussion of the 1-bp deletion (c.2624delT) in exon 18 of the HPS5 gene, causing a frameshift predicted to result in a premature termination codon, that was found in compound heterozygous state in a boy with Hermansky-Pudlak syndrome (HPS5; 614074) by Huizing et al. (2004), see 607521.0002.
Stephen et al. (2017) stated that the c.2624delT (c.2624delT, NM_181507.1) mutation in the patient reported by Huizing et al. (2004) resulted in a frameshift and premature termination (Leu875CysfsTer20).
In a 21-year-old English/Irish woman (patient 113) with Hermansky-Pudlak syndrome (HPS5; 614074), Huizing et al. (2004) identified compound heterozygosity for 2 mutations in the HPS5 gene: a 1-bp insertion (c.879insC) in exon 8 of the HPS5 gene, and a 2-bp (GA) insertion (607521.0005) in exon 20, both causing frameshifts predicted to result in premature termination codons. Northern blot of mRNA isolated from patient fibroblasts showed reduced amounts of HPS5 transcripts, consistent with nonsense-mediated RNA decay.
Stephen et al. (2017) stated that the mutation in this patient reported by Huizing et al. (2004) was c.879dupC (c.879dupC, NM_181507.1), resulting in a frameshift and premature termination (Lys294GlnfsTer6).
For discussion of the 2-bp (GA) insertion in exon 20 of the HPS5 gene, causing a frameshift predicted to result in a premature termination codon, that was found in compound heterozygous state in a woman with Hermansky-Pudlak syndrome (HPS5; 614074) by Huizing et al. (2004), see 607521.0004. Stephen et al. (2017) stated that the mutation in this patient was c.2928_2929dupGA (c.2928_2929dupGA, NM_181507.1), resulting in a frameshift and premature termination (Thr977ArgfsTer15).
In a 92-year-old man with Hermansky-Pudlak syndrome (HPS5; 614074), Ringeisen et al. (2013) identified homozygosity for a 1-bp deletion in the HPS5 gene, causing a frameshift. Ringeisen et al. (2013) designated the mutation c.1081delC, based on HPS5 variant 2 (NM_007216). Summers et al. (2014) noted that the mutation based on HPS5 variant 1 is c.1423delC (c.1423delC, NM_181507.1.), resulting in a frameshift and premature termination (Leu475SerfsTer37).
In a 27-year-old Turkish man with Hermansky-Pudlak syndrome (HPS5; 614074), born of first-cousin parents, Stephen et al. (2017) identified homozygosity for a c.285-10A-G transition (c.285-10A-G, NM_181507.1) in intron 4 of the HPS5 gene, predicted to activate a cryptic acceptor splice site 9 nucleotides before the usual acceptor site. Sanger sequencing of patient fibroblast DNA confirmed the insertion of 9 nucleotides from the intronic region into the coding frame, predicted to result in an in-frame insertion of 3 amino acids (Ser95_Gln96insSerCysSer) in the highly conserved domain of HPS5. Parental DNA was unavailable, and the intron 4 variant was found in the ExAC database as a heterozygous change at an allele frequency of 0.0001. Relative quantification of mRNA from patient fibroblasts showed significant reductions in transcript for the 3 different isoforms of HPS5, with isoforms 1, 2, and 3 being reduced to 40%, 72%, and 65% of control levels, respectively. In addition, Western blot analysis showed severely reduced HPS5 protein levels, as well as slightly reduced expression of HPS6 (607522), in the patient compared to control.
Huizing, M., Hess, R. Dorward, H., Claassen, D. A., Helip-Wooley, A., Kleta, R., Kaiser-Kupfer, M. I., White, J. G., Gahl, W. A. Cellular, molecular and clinical characterization of patients with Hermansky-Pudlak syndrome type 5. Traffic 5: 711-722, 2004. [PubMed: 15296495] [Full Text: https://doi.org/10.1111/j.1600-0854.2004.00208.x]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 63-70, 1999. [PubMed: 10231032] [Full Text: https://doi.org/10.1093/dnares/6.1.63]
Ringeisen, A. L., Schimmenti, L. A., White, J. G., Schoonveld, C., Summers, C. G. Hermansky-Pudlak syndrome (HPS5) in a nonagenarian. J. AAPOS 17: 334-336, 2013. [PubMed: 23607980] [Full Text: https://doi.org/10.1016/j.jaapos.2013.02.002]
Stephen, J., Yokoyama, T., Tolman, N. J., O'Brien, K. J., Nicoli, E.-R., Brooks, B. P., Huryn, L. Titus, S. A., Adams, D. R., Chen, D., Gahl, W. A., Gochuico, B. R., Christine, M., Malicdan, V. Cellular and molecular defects in a patient with Hermansky-Pudlak syndrome type 5. PLoS One 12: e0173682, 2017. Note: Electronic Article. [PubMed: 28296950] [Full Text: https://doi.org/10.1371/journal.pone.0173682]
Summers, C. G., Schimmenti, L. A., Sperber, S. Hermansky-Pudlak syndrome (HPS5) in a nonagenarian. (Letter) J. AAPOS 18: 209-210, 2014. [PubMed: 24698632] [Full Text: https://doi.org/10.1016/j.jaapos.2014.02.002]
Wixler, V., Laplantine, E., Geerts, D., Sonnenberg, A., Petersohn, D., Eckes, B., Paulsson, M., Aumailley, M. Identification of novel interaction partners for the conserved membrane proximal region of alpha-integrin cytoplasmic domains. FEBS Lett. 445: 351-355, 1999. [PubMed: 10094488] [Full Text: https://doi.org/10.1016/s0014-5793(99)00151-9]
Zhang, Q., Zhao, B., Li, W., Oiso, N., Novak, E. K., Rusiniak, M. E., Gautam, R., Chintala, S., O'Brien, E. P., Zhang, Y., Roe, B. A., Elliott, R. W., and 9 others. Ru2 and Ru encode mouse orthologs of the genes mutated in human Hermansky-Pudlak syndrome types 5 and 6. Nature Genet. 33: 145-154, 2003. [PubMed: 12548288] [Full Text: https://doi.org/10.1038/ng1087]