Alternative titles; symbols
HGNC Approved Gene Symbol: HPS6
Cytogenetic location: 10q24.32 Genomic coordinates (GRCh38) : 10:102,065,349-102,068,036 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q24.32 | Hermansky-Pudlak syndrome 6 | 614075 | Autosomal recessive | 3 |
The HPS6 gene encodes a protein involved in the biogenesis of lysosome-related organelles complex-2 (BLOC2) (Zhang et al., 2003).
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; 607521) and ruby-eye (ru), 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 ru ortholog contains 775 amino acids and is 80% identical to the mouse protein. Northern blot analysis of mouse tissues detected a 2.6-kb ru transcript in all tissues tested, with lowest expression in skeletal muscle. Zhang et al. (2003) concluded that ru and ru2 represent a novel class of genes that have evolved in higher organisms to govern the synthesis of highly specialized lysosome-related organelles.
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 genomic sequence analysis, Zhang et al. (2003) determined that a single large exon contains the entire open reading frame in both the mouse ru gene and the human HPS6 gene.
By genomic sequence analysis, Zhang et al. (2003) mapped the mouse ru gene to chromosome 19 and the human HPS6 gene to chromosome 10q24.32.
In a 39-year-old Belgian woman with Hermansky-Pudlak syndrome (HPS6; 614075), Zhang et al. (2003) identified a homozygous 4-bp deletion (607522.0001) in the HPS6 gene.
In affected members of a large consanguineous Israeli Bedouin family with Hermansky-Pudlak syndrome, who exhibited primarily oculocutaneous albinism, Schreyer-Shafir et al. (2006) identified homozygosity for a 1-bp insertion in the HPS6 gene (607522.0002).
Huizing et al. (2009) identified homozygous or compound heterozygous mutations (607522.0003-607522.0007) in the HPS6 gene in 4 unrelated patients with Hermansky-Pudlak syndrome. All mutations except 1 resulted in a truncated protein. The phenotype was characterized by early-onset nystagmus, oculocutaneous albinism, and a mild bleeding diathesis, but no pulmonary fibrosis, granulomatous colitis, or renal involvement. However, 2 patients had gastrointestinal symptoms. In vitro cellular studies performed on patient melanocytes indicated aberrant cytoplasmic distribution patterns of melanogenic proteins and increased trafficking of TYRP1 (115501) through the plasma membrane, indicating a defect in lysosomal-related organelles.
In 2 Japanese sisters with oculocutaneous albinism and absence of platelet dense bodies, Miyamichi et al. (2016) identified compound heterozygosity for a 1-bp deletion (607522.0009) and a nonsense mutation (Q680X; 607522.0010) in the HPS6 gene.
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 39-year-old Belgian woman with Hermansky-Pudlak syndrome (HPS6; 614075), Zhang et al. (2003) identified homozygosity for a 4-bp deletion (TCTG) at codons cys571 to leu572 of the HPS6 gene. The mutation resulted in a frameshift with truncation of the nonsense polypeptide at codon 610, causing loss of 30% of the protein at the C terminus.
In affected members of a large consanguineous Israeli Bedouin family with Hermansky-Pudlak syndrome-6 (HPS6; 614075), Schreyer-Shafir et al. (2006) identified a homozygous 1-bp insertion (1066insG) in the HPS6 gene. Expression studies did not show nonsense-mediated mRNA decay, so a truncated protein was likely produced. The phenotype was somewhat unique in that it was characterized mainly by oculocutaneous albinism. Electron microscopic studies of platelets showed absence of dense bodies, consistent with HPS, and confocal microscopy revealed abnormal distribution of LAMP3 (605883) in patient fibroblasts, indicating abnormal trafficking of lysosomal-related organelles. The findings expanded the phenotype associated with mutations in the HPS6 gene.
In a 36-year-old woman of Irish and German descent with Hermansky-Pudlak syndrome-6 (HPS6; 614075), Huizing et al. (2009) identified a homozygous 2-bp deletion (1865delTG) in the HPS6 gene, resulting in a frameshift, premature termination, and loss of about 20% of the protein at the 3-prime end. As well as partial albinism, nystagmus, and bleeding complications, this patient also had had multiple abdominal surgeries for hernia, imperforate anus, and gluteal flap repairs. She had other medical problems, including 4 miscarriages, endometriosis, frequent upper respiratory and urinary tract infections, incontinence, migraine headaches, and hearing loss. However, she did not have granulomatous colitis, and renal and pulmonary functions were normal.
In a 22-year-old man of northern European descent with Hermansky-Pudlak syndrome-6 (HPS6; 614075), Huizing et al. (2009) identified compound heterozygosity for a 913C-T transition in the HPS6 gene, resulting in a gln305-to-ter (Q305X) substitution, and a large 20-kb deletion encompassing the HPS6 gene. He had nystagmus at birth and was diagnosed with oculocutaneous albinism at age 3 months. HPS was diagnosed at age 16 years.
In a 13-year-old girl of German and Dutch descent with Hermansky-Pudlak syndrome-6 (HPS6; 614075), Huizing et al. (2009) identified compound heterozygosity for 2 mutations in the HPS6 gene: a 1-bp duplication (238dupG), resulting in a frameshift and premature termination, and an 815C-T transition, resulting in a thr272-to-ile (T272I; 607522.0006) substitution in a highly conserved region. The T272I mutation was not found in 484 control chromosomes.
For discussion of the thr272-to-ile (T272I) mutation in the HPS6 gene that was found in compound heterozygous state in a patient with Hermansky-Pudlak syndrome-6 (HPS6; 614075) by Huizing et al. (2009), see 607522.0005.
In a 52-year-old Italian man with Hermansky-Pudlak syndrome-6 (HPS6; 614075), Huizing et al. (2009) identified compound heterozygosity for 2 mutations in the HPS6 gene: a 223C-T transition, resulting in a gln75-to-ter (Q75X) substitution, and a 1234C-T transition, resulting in a gln412-to-ter (Q412X; 607522.0008) substitution. He had rotary nystagmus at birth and bruising in childhood, but was only diagnosed at age 44 years when he was found to have gastrointestinal symptoms and oculocutaneous albinism. Laboratory studies showed iron-deficiency anemia and low vitamin B12. There was no interstitial lung disease or renal involvement. Two sisters were reportedly affected.
For discussion of the gln412-to-ter (Q412X) mutation in the HPS6 gene that was found in compound heterozygous state in a patient with Hermansky-Pudlak syndrome-6 (HPS6; 614075) by Huizing et al. (2009), see 607522.0007.
In 2 Japanese sisters with Hermansky-Pudlak syndrome-6 (HPS6; 614075), manifested by oculocutaneous albinism and absence of platelet dense bodies, Miyamichi et al. (2016) identified compound heterozygosity for mutations in the HPS6 gene: a 1-bp deletion (c.1898delC, NM_024747.5), causing a frameshift predicted to result in a premature termination codon (Pro633LeufsTer76), and a c.2038C-T transition, resulting in a gln680-to-ter (Q680X; 607522.0010) substitution. Their unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 575 in-house exomes or the ExAC or Exome Variant Server databases. However, the Q680X variant was found at an allele frequency of 0.003 in the Human Genetic Variation database.
For discussion of the c.2038C-T transition (c.2038C-T, NM_024747.5) in the HPS6 gene, resulting in a gln680-to-ter (Q680X) substitution, that was found in compound heterozygous state in 2 Japanese sisters with Hermansky-Pudlak syndrome-6 (HPS6; 614075) by Miyamichi et al. (2016), see 607522.0009.
Huizing, M., Pederson, B., Hess, R. A., Griffin, A., Helip-Wooley, A., Westbroek, W., Dorward, H., O'Brien, K. J., Golas, G., Tsilou, E., White, J. G., Gahl, W. A. Clinical and cellular characterisation of Hermansky-Pudlak syndrome type 6. J. Med. Genet. 46: 803-810, 2009. [PubMed: 19843503] [Full Text: https://doi.org/10.1136/jmg.2008.065961]
Miyamichi, D., Asahina, M., Nakajima, J., Sato, M., Hosono, K., Nomura, T., Negishi, T., Miyake, N., Hotta, Y., Ogata, T., Matsumoto, N. Novel HPS6 mutations identified by whole-exome sequencing in two Japanese sisters with suspected ocular albinism. J. Hum. Genet. 61: 839-842, 2016. [PubMed: 27225848] [Full Text: https://doi.org/10.1038/jhg.2016.56]
Schreyer-Shafir, N., Huizing, M., Anikster, Y., Nusinker, Z., Bejarano-Achache, I., Maftzir, G., Resnik, L., Helip-Wooley, A., Westbroek, W., Gradstein, L., Rosenmann, A., Blumenfeld, A. A new genetic isolate with a unique phenotype of syndromic oculocutaneous albinism: clinical, molecular, and cellular characteristics. (Abstract) Hum. Mutat. 27: 1158 only, 2006. Note: Full article online. [PubMed: 17041891] [Full Text: https://doi.org/10.1002/humu.9463]
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]