Alternative titles; symbols
HGNC Approved Gene Symbol: BLOC1S6
Cytogenetic location: 15q21.1 Genomic coordinates (GRCh38) : 15:45,587,123-45,609,716 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q21.1 | Hermansky-Pudlak syndrome 9 | 614171 | Autosomal recessive | 3 |
The 'pallid' mouse mutant represents a platelet storage pool deficiency (SPD) manifesting with prolonged bleeding time, pigment dilution, and other features. Huang et al. (1999) described the physical mapping, positional cloning, and mutational and functional analysis of the gene that is defective in pallid mice. The gene encodes a ubiquitously expressed, highly charged 172-amino acid protein, which they called pallidin, with no homology to known proteins. Huang et al. (1999) isolated the orthologous gene encoding human pallidin and found that the predicted protein has 86% amino acid identity with the mouse protein. The first 60 amino acids give rise to an unstructured protein, followed by 2 highly alpha-helical coiled-coil regions, essential for pallidin self-binding and binding to syntaxin-13 (see STX12, 606892).
Cullinane et al. (2011) noted that PLDN transcript-1, which they called PLDN1, contains 172 amino acids and is encoded by exons 1 to 5. Transcript-2, which they called PLDN2, contains 101 amino acids and is encoded by exon A, exon 2, and exon B. PCR analysis of adult and fetal human tissues showed ubiquitous expression of transcript-1 except for absence in adult and fetal brain. Transcript-2 showed limited expression in adult brain, testis, and leukocytes, and in fetal lung, brain, and thymus.
Cullinane et al. (2011) determined that the PLDN gene contains 7 exons with alternative splicing of exons A and B.
Huang (2000) stated that ESTs of the human PLDN gene had been mapped to chromosome 15q15 by radiation hybrid mapping.
By ancestral chromosome mapping, Huang et al. (1999) localized the mouse pallidin gene to chromosome 2E. The pallidin gene is closely linked to mouse Epb42 (177070) and B2m (109700), 68 cM from the centromere.
Using a yeast 2-hybrid screen, Huang et al. (1999) discovered that pallidin interacts with syntaxin-13 (see STX12, 606892), a t-SNARE protein that mediates vesicle docking and fusion. Huang et al. (1999) confirmed this interaction by coimmunoprecipitation assay. Immunofluorescence studies corroborated that the cellular distribution of pallidin overlaps that of syntaxin-13.
By coimmunoprecipitation and immunodepletion experiments of mouse skin fibroblasts, Falcon-Perez et al. (2002) identified pallidin as a component of BLOC1 (biogenesis of lysosome-related organelles complex-1; see 601444), which also contains 'muted' (607289). A yeast 2-hybrid screen found no direct interaction between muted and pallidin, but pallidin was found to interact with itself. Residues that include 2 putative coiled-coil domains of human pallidin were necessary and sufficient for self-assembly. Falcon-Perez et al. (2002) also determined that pallidin/BLOC1 could interact with actin filaments in vitro and in transfected cells.
In a 17-year-old Italian girl with Hermansky-Pudlak syndrome-9 (HPS9; 614171), with clinical features of oculocutaneous albinism, nystagmus, thrombocytopenia, and primary immunodeficiency, Badolato et al. (2012) performed whole-exome sequencing (WES) and identified homozygosity for a gln78-to-ter mutation (Q78X; 604310.0001) in the PLDN gene; no mutations were found in other immunodeficiency-associated genes.
By WES in a 4-year-old Pakistani girl with HPS9, Yousaf et al. (2016) identified homozygosity for the previously reported Q78X nonsense mutation in the BLOC1S6 gene. Her unaffected consanguineous parents were heterozygous for the mutation.
In a 52-year-old Japanese woman with HPS9, Okamura et al. (2018) identified homozygosity for a 2-bp duplication in the BLOC1S6 gene (604310.0002) that segregated with disease in the family.
In a 2.5-year-old girl of Syrian origin with HPS9, Michaud et al. (2021) performed next-generation sequencing of 19 albinism-associated genes and identified compound heterozygous mutations in the BLOC1S6 gene: a nonsense mutation (S67X; 604310.0003) and a 2-bp deletion/insertion (604310.0004) that segregated with disease in the family.
In a 6-year-old Chinese boy with HPS9, Liu et al. (2021) identified compound heterozygosity for mutations in the BLOC1S6 gene: a nonsense mutation (E50X; 604310.0005) and a 1-bp duplication (604310.0006) that segregated with disease.
'Pallid' is 1 of 13 platelet SPD mouse mutants. Pallid (pa) animals suffer from prolonged bleeding time, pigment dilution, kidney lysosomal enzyme elevation, serum alpha-1-antitrypsin activity deficiency (613490), and abnormal otolith formation. As with other mouse mutants of this class, characterization of pallid mice suggested a defect in organelle biosynthesis. Huang et al. (1999) detected a nonsense mutation at codon 69 of this gene in the pallid mutant. Whereas the 'mocha' (607246) and 'pearl' (603401) SPD mutants have defects in Ap3, the findings of Huang et al. (1999) suggested that pallid SPD mutants are defective in a more downstream event of vesicle trafficking, namely vesicle docking and fusion. Huang et al. (1999) stated that pallid was the fifth SPD mutant to be described at the molecular level. These mutants are characterized by abnormalities in platelet-dense granules, melanosomes, and lysosomes, and in each case, the predicted protein is involved in organelle biogenesis.
Cullinane et al. (2011) reported a child with an HPS-like syndrome and a homozygous Q78X mutation in the PLDN gene; however, this article was retracted based on the finding of the United States Office of Research Integrity that Andrew R. Cullinane, Ph.D., 'falsified and/or fabricated the results in Figure 3C, by using the same gel images to represent expression of PLDN in fibroblasts and melanocytes.'
In a 17-year-old Italian girl with Hermansky-Pudlak syndrome-9 (HPS9; 614171), Badolato et al. (2012) performed whole-exome sequencing and identified homozygosity for a c.232C-T transition (chr15.45,895,305C-T, GRCh37) in exon 3 of the PLDN gene, resulting in a gln78-to-ter (Q78X) substitution. Sanger sequencing confirmed the mutation, which was present in heterozygosity in her unaffected parents and was not found in 50 geographically matched control individuals, in approximately 250 control exomes, or in the NHLBI exome collection.
In a 4-year-old Pakistani girl (family LUAB11) with HPS9, Yousaf et al. (2016) identified homozygosity for the previously reported Q78X mutation in the BLOC1S6 gene. Her unaffected consanguineous parents were heterozygous for the mutation.
In a 52-year-old Japanese woman (patient 3) with Hermansky-Pudlak syndrome-9 (HPS9; 614171), Okamura et al. (2018) identified homozygosity for a 2-bp duplication (c.285_286dupTC, NM_012388.3) in the BLOC1S6 gene, causing a frameshift predicted to result in a premature termination codon (His96LeufsTer22). Her unaffected mother and sister were heterozygous for the mutation; DNA was unavailable from her father, who was her mother's third cousin.
In a 2.5-year-old Syrian girl with Hermansky-Pudlak syndrome-9 (HPS9; 614171), Michaud et al. (2021) identified compound heterozygosity for mutations in the BLOC1S6 gene: a c.200C-G transversion (c.200C-G, NM_012388.3) in exon 2, resulting in a ser67-to-ter (S67X) substitution, and an insertion/deletion (c.319_320delGAinsAT) in exon 4, resulting in a glu107-to-met (E107M; 604310.0004) substitution. Her unaffected parents were each heterozygous for 1 of the mutations; the insertion/deletion was not found in the gnomAD database, whereas the nonsense mutation was present once, in heterozygosity.
For discussion of the insertion/deletion mutation (c.319_320delGAinsAT, NM_012388.3) in exon 4 of the BLOC1S6 gene, resulting in a glu107-to-met (E107M) substitution, that was found in compound heterozygous state in a 2.5-year-old Syrian girl with Hermansky-Pudlak syndrome-9 (HPS9; 614171) by Michaud et al. (2021), see 604310.0003.
In a 6-year-old Chinese boy with Hermansky-Pudlak syndrome-9 (HPS9; 614171), Liu et al. (2021) identified compound heterozygosity for mutations in the BLOC1S6 gene: a c.148G-T transversion, resulting in a glu50-to-ter (E50X) substitution, and a 1-bp duplication (c.351dupT), causing a frameshift predicted to result in a premature termination codon (Ile118TyrfsTer10). His unaffected parents were each heterozygous for 1 of the mutations. Western blot assays showed absence of pallidin protein in the proband compared to his parents, and another BLOC1 subunit, dysbindin-1a (see 607145), was reduced in the proband, suggesting dysfunction of BLOC1.
For discussion of the 1-bp duplication (c.351dupT) in the BLOC1S6 gene that was found in compound heterozygous state in a 6-year-old Chinese boy with Hermansky-Pudlak syndrome-9 (HPS9; 614171) by Liu et al. (2021), see 604310.0005.
Badolato, R., Prandini, A., Caracciolo, S., Colombo, F., Tabellini, G., Giacomelli, M., Cantarini, M. E., Pession, A., Bell, C. J., Dinwiddie, D. L., Miller, N. A., Hateley, S. L., Saunders, C. J., Zhang, L., Schroth, G. P., Plebani, A., Parolini, S., Kingsmore, S. F. Exome sequencing reveals a pallidin mutation in a Hermansky-Pudlak-like primary immunodeficiency syndrome. (Letter) Blood 119: 3185-3187, 2012. [PubMed: 22461475] [Full Text: https://doi.org/10.1182/blood-2012-01-404350]
Cullinane, A. R., Curry, J. A., Carmona-Rivera, C., Summers, C. G., Ciccone, C., Cardillo, N. D., Dorward, H., Hess, R. A., White, J. G., Adams, D., Huizing, M., Gahl, W. A. A BLOC-1 mutation screen reveals that PLDN is mutated in Hermansky-Pudlak syndrome type 9. Am. J. Hum. Genet. 88: 778-787, 2011. Note: Retraction. Am. J. Hum. Genet. 100: 837 only, 2017. [PubMed: 21665000] [Full Text: https://doi.org/10.1016/j.ajhg.2011.05.009]
Falcon-Perez, J. M., Starcevic, M., Gautam, R., Dell'Angelica, E. C. BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules. J. Biol. Chem. 277: 28191-28199, 2002. [PubMed: 12019270] [Full Text: https://doi.org/10.1074/jbc.M204011200]
Huang, L., Kuo, Y.-M., Gitschier, J. The pallid gene encodes a novel, syntaxin 13-interacting protein involved in platelet storage pool deficiency. Nature Genet. 23: 329-332, 1999. [PubMed: 10610180] [Full Text: https://doi.org/10.1038/15507]
Huang, L. Personal Communication. San Francisco, Calif. 2/3/2000.
Liu, T., Yuan, Y., Bai, D., Yao, X., Zhang, T., Huang, Q., Qi, Z., Yang, L., Yang, X., Li, W., Wei, A. The first Hermansky-Pudlak syndrome type 9 patient with two novel variants in Chinese population. J. Derm. 48: 676-680, 2021. [PubMed: 33543539] [Full Text: https://doi.org/10.1111/1346-8138.15762]
Michaud, V., Fiore, M., Coste, V., Huguenin, Y., Bordet, J.-C., Plaisant, C., Lasseaux, E., Morice-Picard, F., Arveiler, B. A new case with Hermansky-Pudlak syndrome type 9, a rare cause of syndromic albinism with severe defect of platelets dense bodies. Platelets 32: 420-423, 2021. [PubMed: 32245340] [Full Text: https://doi.org/10.1080/09537104.2020.1742315]
Okamura, K., Abe, Y., Araki, Y., Wakamatsu, K., Seishima, M., Umetsu, T., Kato, A., Kawaguchi, M., Hayashi, M., Hozumi, Y., Suzuki, T. Characterization of melanosomes and melanin in Japanese patients with Hermansky-Pudlak syndrome types 1, 4, 6, and 9. Pigment Cell Melanoma Res. 31: 267-276, 2018. [PubMed: 29054114] [Full Text: https://doi.org/10.1111/pcmr.12662]
Yousaf, S., Shahzad, M., Kausar, T., Sheikh, S. A., Tariq, N., Shabbir, A. S., University of Washington Center for Mendelian Genomics, Ali, M., Waryah, A. M., Shaikh, R. S., Riazuddin, S., Ahmed, Z. M. Identification and clinical characterization of Hermansky-Pudlak syndrome alleles in the Pakistani population. Pigment Cell Melanoma Res. 29: 231-235, 2016. [PubMed: 26575419] [Full Text: https://doi.org/10.1111/pcmr.12438]