ORPHA: 231531, 231537, 79430; DO: 0060546;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19q13.32 | Hermansky-Pudlak syndrome 8 | 614077 | Autosomal recessive | 3 | BLOC1S3 | 609762 |
A number sign (#) is used with this entry because of evidence that Hermansky-Pudlak syndrome-8 (HPS8) is caused by homozygous mutation in the BLOC1S3 gene (609762) on chromosome 19q13.
Hermansky-Pudlak syndrome-8 (HPS8) is a rare autosomal recessive disorder characterized by generalized hypopigmentation, reduced visual acuity, and prolonged bleeding of varying severity. The eye phenotype includes nystagmus, iris transilluminancy, foveal hypoplasia, and evidence of optic pathway misrouting (Morgan et al., 2006, Cullinane et al., 2012).
For a phenotypic description and a discussion of genetic heterogeneity of Hermansky-Pudlak syndrome, see HPS1 (203300).
Morgan et al. (2006) described a large consanguineous Pakistani family in which affected individuals displayed features of incomplete oculocutaneous albinism and platelet dysfunction. Skin biopsy demonstrated abnormal aggregates of melanosomes within basal epidermal keratinocytes. The proband was born with silvery hair that later darkened to a 'gold' color. He had hazel eyes and pale skin that became red but did not tan in the sun. At the age of 21 years no history of bleeding or recurrent infections was noted. On examination, there was generalized hypopigmentation and reduced visual acuity. Eye examination revealed optic disc cupping, pale fundi, and moderate foveal hypoplasia. Visual evoked responses demonstrated increased chiasmal decussation. There was moderate hypermetropia with esotropia. A scalp skin biopsy performed at age 24 years revealed aggregates of abnormally small but fully melanized melanosomes. Morgan et al. (2006) described 5 other members of the family. All had similar features, and several had easy bruising, prolonged or excessive bleeding from wounds, and menorrhagia.
Cullinane et al. (2012) studied a 6-year-old Iranian boy who was born with brown irides, nystagmus, and lighter skin than either of his first-cousin parents. Examination at age 6 years revealed bilateral exotropia and fine horizontal nystagmus; funduscopy showed iris transillumination, moderate pallor of the optic discs, absent foveal reflexes, and decreased pigment in the peripheral retina. He also had easy bruising and minor gum bleeding, and delta granules were absent from his platelets. Analysis of a packed pellet of melanocytes cultured from the patient demonstrated that it was notably lighter than a control pellet. The patient showed no clinical signs of HPS subtype-specific symptoms, such as neutropenia, granulomatous colitis, or pulmonary fibrosis.
The transmission pattern of HPS8 in the family reported by Morgan et al. (2006) was consistent with autosomal recessive inheritance.
Using an autozygosity mapping strategy, Morgan et al. (2006) mapped the HPS phenotype in a consanguineous Pakistani family to chromosome 19q13.
Morgan et al. (2006) noted that the human homolog of the mouse 'reduced pigmentation' (rp) gene, BLOC1S3 (609762), mapped to the target interval identified in a consanguineous Pakistani family with HPS. They identified a homozygous frameshift mutation in the BLOC1S3 gene (609762.0001) in all affected individuals in the family.
In 38 patients with HPS, who were known to be negative for mutation in genes related to the AP3, BLOC2, and BLOC3 protein complexes, Cullinane et al. (2012) screened the 8 BLOC1-associated genes and identified homozygosity for a nonsense mutation in the BLOC1S3 gene (S44X; 609762.0002) in a 6-year-old Iranian boy.
Starcevic and Dell'Angelica (2004) determined that the reduced pigmentation (rp) mutation in mice, a model of HPS, results from a 1-bp substitution (238C-T) in the Blos3 gene (BLOC1S3). The mutation introduces a premature termination codon (Q80X) in rp mice. A frameshift mutation in the BLOC1S3 gene was subsequently found in individuals with HPS (609762.0001). While eye pigment formation was reported to be normal in the rp mouse, visual defects (nystagmus, iris transillumination, foveal hypoplasia, reduced visual acuity, and evidence of optic pathway misrouting) were found in individuals with mutations in BLOC1S3.
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]
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]