ORPHA: 231531, 79430; DO: 0060545;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p22.3 | Hermansky-Pudlak syndrome 7 | 614076 | Autosomal recessive | 3 | DTNBP1 | 607145 |
A number sign (#) is used with this entry because of evidence that Hermansky-Pudlak syndrome-7 (HPS7) is caused by homozygous mutation in the DTNBP1 gene (607145) on chromosome 6p22.
Hermansky-Pudlak syndrome-7 (HPS7) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and prolonged bleeding. Granulomatous colitis has also been reported (Li et al., 2003, Lowe et al., 2013).
For a phenotypic description and a discussion of genetic heterogeneity of Hermansky-Pudlak syndrome, see HPS1 (203300).
Li et al. (2003) identified a 48-year-old Portuguese woman with Hermansky-Pudlak syndrome. She exhibited oculocutaneous albinism, ease of bruising, and a bleeding tendency. Bleeding time was 13 minutes, and platelet aggregation indicated a storage-pool deficiency. The woman had mild shortness of breath on exertion and reduced lung compliance but otherwise normal pulmonary function and high resolution computed tomography (CT) chest scans, and had no muscle weakness or ataxia. Her parents were first cousins.
Lowe et al. (2013) reported a 77-year-old Caucasian woman, born of consanguineous parents, with HPS. The patient had a lifelong bleeding tendency, including spontaneous epistaxis, prolonged bleeding after dental extractions and minor surgical procedures, menorrhagia, heavy postpartum bleeding, and perirectal bleeding. She also had pale skin and hair, as well as lifelong reduced visual acuity and nystagmus. She had no evidence of pulmonary disease but did have granulomatous colitis diagnosed as Crohn disease. Platelet studies showed impaired aggregation responses and a lack of dense granule secretion.
Bryan et al. (2017) reported a 6-year-old Paraguayan boy with HPS. The boy had ocular albinism, nystagmus, and easy bruising with trauma-induced intracranial hemorrhage. He had some skin and hair pigmentation but was paler than his parents. Electron microscopy showed absent dense granules, and platelet aggregation studies were abnormal. He had delayed motor and language development, fundus hypopigmentation, foveal hypoplasia, optic nerve hypoplasia, and hyperopic astigmatism. He had no recurrent or unusual infections. There was no interstitial lung disease on imaging and lung function was normal. There was no known history of consanguinity.
The transmission pattern of HPS7 in the families reported by Li et al. (2003) and Lowe et al. (2013) was consistent with autosomal recessive inheritance.
The gene mutant in HPS7, DTNBP1, maps to chromosome 6p22.3 (Li et al., 2003).
Swank et al. (1991) demonstrated that the 'sandy' (sdy) mutant mouse is a valid model for human HPS and mapped the sdy locus to mouse chromosome 13.
Li et al. (2003) showed that mutation in the dysbindin gene, Dtnbp1, causes the sdy phenotype in mice. In a 48-year-old Portuguese woman with Hermansky-Pudlak syndrome, Li et al. (2003) identified homozygosity for a nonsense mutation in the DTNBP1 gene (Q103X; 607145.0001).
In a 77-year-old Caucasian woman, born of consanguineous parents, with HPS7, Lowe et al. (2013) identified a homozygous truncating mutation in the DTNBP1 gene (W59X; 607145.0002). The mutation was found by autozygosity mapping with microsatellite markers followed by direct sequencing of the candidate DTNBP1 gene.
In a 6-year-old Paraguayan boy with HPS7, Bryan et al. (2017) identified homozygosity for the previously identified Q103X mutation in the DTNBP1 gene. Patient fibroblasts showed normal DTNBP1 mRNA expression but negligible dysbindin protein expression.
In mice, at least 16 loci are associated with HPS, including 'sandy' (sdy) (Swank et al., 1991). Li et al. (2003) showed that the sdy mutant mouse expresses no dysbindin protein owing to a deletion in the gene Dtnbp1. They confirmed that mutation of dysbindin causes the sdy phenotype and that dysbindin is important for normal platelet-dense granule and melanosome biogenesis. Li et al. (2003) showed that dysbindin is a component of the biogenesis of lysosome-related organelles complex-1 (BLOC1), which regulates trafficking to lysosome-related organelles and includes the proteins pallidin (604310), muted (607289), and cappuccino (605695), all of which are associated with Hermansky-Pudlak syndrome in mice.
Bryan, M. M., Tolman, N. J., Simon, K. L., Huizing, M., Hufnagel, R. B., Brooks, B. P., Speransky, V., Mullikin, J. C., Gahl, W. A., Malicdan, M. C. V., Gochuico, B. R. Clinical and molecular phenotyping of a child with Hermansky-Pudlak syndrome-7, an uncommon genetic type of HPS. Molec. Genet. Metab. 120: 378-383, 2017. [PubMed: 28259707] [Full Text: https://doi.org/10.1016/j.ymgme.2017.02.007]
Li, W., Zhang, Q., Oiso, N., Novak, E. K., Gautam, R., O'Brien, E. P., Tinsley, C. L., Blake, D. J., Spritz, R. A., Copeland, N. G., Jenkins, N. A., Amato, D., Roe, B. A., Starcevic, M., Dell'Angelica, E. C., Elliott, R. W., Mishra, V., Kingsmore, S. F., Paylor, R. E., Swank, R. T. Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Nature Genet. 35: 84-89, 2003. [PubMed: 12923531] [Full Text: https://doi.org/10.1038/ng1229]
Lowe, G. C., Sanchez Guiu, I., Chapman, O., Rivera, J., Lordkipanidze, M., Dovlatova, N., Wilde, J., Watson, S. P., Morgan, N. V. Microsatellite markers as a rapid approach for autozygosity mapping in Hermansky-Pudlak syndrome: identification of the second HPS7 mutation in a patient presenting late in life. (Letter) Thromb. Haemost. 109: 766-768, 2013. [PubMed: 23364359] [Full Text: https://doi.org/10.1160/TH12-11-0876]
Swank, R. T., Sweet, H. O., Davisson, M. T., Reddington, M., Novak, E. K. Sandy: a new mouse model for platelet storage pool deficiency. Genet. Res. 58: 51-62, 1991. [PubMed: 1936982] [Full Text: https://doi.org/10.1017/s0016672300029608]