Alternative titles; symbols
HGNC Approved Gene Symbol: BLOC1S3
Cytogenetic location: 19q13.32 Genomic coordinates (GRCh38) : 19:45,178,784-45,217,083 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.32 | Hermansky-Pudlak syndrome 8 | 614077 | Autosomal recessive | 3 |
BLOC1S3 is a component of the ubiquitously expressed BLOC1 multisubunit protein complex. BLOC1 is required for normal biogenesis of specialized organelles of the endosomal-lysosomal system, such as melanosomes and platelet dense granules (Starcevic and Dell'Angelica, 2004).
Using the BLOC1 subunit pallidin (BLOC1S6; 604310) as bait in a yeast 2-hybrid screen of a HeLa cell cDNA library, Starcevic and Dell'Angelica (2004) cloned BLOC1S3, which they called BLOS3. The deduced BLOS3 protein has a calculated molecular mass of 21.3 kD. However, Western blot analysis detected endogenous HeLa cell BLOS3 at an apparent molecular mass of 32 kD.
Gross (2017) mapped the BLOC1S3 gene to chromosome 19q13.32 based on an alignment of the BLOC1S3 sequence (GenBank AY531266) with the genomic sequence (GRCh38).
Starcevic and Dell'Angelica (2004) mapped the mouse Bloc1s3 gene to chromosome 7A2.
By mass spectrometry of BLOC1 proteins purified from bovine liver, mouse liver, and HeLa cells, Starcevic and Dell'Angelica (2004) identified BLOS3 as a subunit of BLOC1. Other BLOC1 subunits identified were pallidin, muted (607289), dysbindin (DTNBP1; 607145), cappuccino (BLOC1S4; 605695), snapin (SNAPIN; 607007), BLOC1S1 (601444), and BLOC1S2 (609768). Coimmunoprecipitation and yeast 2-hybrid analyses confirmed that these proteins interact within the BLOC1 complex.
Cullinane et al. (2012) performed immunoblot analysis of BLOC1 subunits in fibroblast lysates from a control and from Hermansky-Pudlak syndrome-8 (HPS8; 614077) and HPS9 (614171) patients with mutations in the BLOC1S3 and pallidin (BLOC1S6; 604310) genes, respectively. The HPS8 patient showed a reduction in pallidin to 55% of control, as well as absence of the cappuccino and dysbindin subunits and a reduction in snapin to 53% of control. The HPS9 patient also showed absence of cappuccino and dysbindin, and snapin was reduced to 59% of control. The authors suggested that when any member of the BLOC1 complex is mutated, the whole complex is unstable and prone to degradation. Both patients showed normal protein expression for the HPS5 (607521) and HPS4 (606682) genes, subunits of the BLOC2 and BLOC3 complexes, respectively, thus confirming that the BLOC2 and BLOC3 complexes are normally expressed and form independently in BLOC1-deficient patients.
Using an autozygosity mapping strategy, Morgan et al. (2006) mapped Hermansky-Pudlak syndrome (HPS8; 614077) in a large consanguineous family to 19q13. Affected individuals displayed features of incomplete oculocutaneous albinism and platelet dysfunction. Skin biopsy demonstrated abnormal aggregates of melanosomes within basal epidermal keratinocytes. Morgan et al. (2006) noted that the human homolog of the rp gene, which is disrupted in a mouse model of Hermansky-Pudlak syndrome, resides in this region. Sequencing of the single exon of the BLOC1S gene demonstrated a 1-bp frameshift deletion, 448delC (609762.0001).
In a 6-year-old Iranian boy with HPS, Cullinane et al. (2012) identified homozygosity for a nonsense mutation in the BLOC1S3 gene (S44X; 609762.0002).
Starcevic and Dell'Angelica (2004) determined that the reduced pigmentation (rp) mutation in mice, a model of Hermansky-Pudlak syndrome (HPS; 203300), results from a 1-bp substitution (238C-T) in the Blos3 gene. The mutation introduces a premature termination codon (Q80X) in rp mice. Mutant mRNA was not subject to nonsense-mediated mRNA decay. The rp mutation did not completely disrupt BLOC1 assembly.
In a man of Pakistani extraction with Hermansky-Pudlak syndrome (HPS8; 614077) whose parents were first cousins, Morgan et al. (2006) described a 1-bp frameshift mutation in the BLOC1S3 gene (448delC). He was referred at the age of 21 years for genetic counseling for 'oculocutaneous albinism.' He was born with silvery hair, which slowly darkened to a 'gold' color, and he had hazel eyes and pale skin that became red but did not tan in the sun. There was no history of bleeding or recurrent infections. There was generalized hypopigmentation and reduced visual acuity with pendular nystagmus and iris transillumination. Visual evoked responses demonstrated increased chiasmal decussation. Other affected members of the family carrying the mutation had histories of easy bruising and prolonged bleeding after cuts, as well as frequent nosebleeds.
In a 6-year-old Iranian boy with Hermansky-Pudlak syndrome (HPS8; 614077), Cullinane et al. (2012) identified homozygosity for a c.131C-A transversion (c.131C-A, NM_212550) in the BLOC1S3 gene, resulting in a ser44-to-ter (S44X) substitution. Quantitative RT-PCR showed that BLOC1S3 mRNA levels in patient fibroblasts and melanocytes were significantly reduced to approximately 6% and 4%, respectively, of those of control cells. Standard PCR of patient cDNA showed no amplification of BLOC1S3 from patient fibroblasts or melanocytes, suggesting nonsense-mediated decay of the mutant transcript. Immunofluorescence microscopy of patient melanocytes showed abnormal accumulation of TYRP1 (115501) in the Golgi region, whereas tyrosinase localized normally and did not appear to significantly accumulate in the Golgi region. The authors suggested that mislocalization in BLOC1S3-deficient cells is cargo-specific.
Cullinane, A. R., Curry, J. A., Golas, G., Pan, J., Carmona-Rivera, C., Hess, R. A., White, J. G., Huizing, M., Gahl, W. A. A BLOC-1 mutation screen reveals a novel BLOC1S3 mutation in Hermansky-Pudlak syndrome type 8. Pigment Cell Melanoma Res. 25: 584-591, 2012. [PubMed: 22709368] [Full Text: https://doi.org/10.1111/j.1755-148X.2012.01029.x]
Gross, M. B. Personal Communication. Baltimore, Md. 8/8/2017.
Morgan, N. V., Pasha, S., Johnson, C. A., Ainsworth, J. R., Eady, R. A. J., Dawood, B., McKeown, C., Trembath, R. C., Wilde, J., Watson, S. P., Maher, E. R. A germline mutation in BLOC1S3/reduced pigmentation causes a novel variant of Hermansky-Pudlak syndrome (HPS8). Am. J. Hum. Genet. 78: 160-166, 2006. [PubMed: 16385460] [Full Text: https://doi.org/10.1086/499338]
Starcevic, M., Dell'Angelica, E. C. Identification of Snapin and three novel proteins (BLOS1, BLOS2, and BLOS3/reduced pigmentation) as subunits of biogenesis of lysosome-related organelles complex-1 (BLOC-1). J. Biol. Chem. 279: 28393-28401, 2004. [PubMed: 15102850] [Full Text: https://doi.org/10.1074/jbc.M402513200]