Hermansky-Pudlak syndrome is caused by mutations in HPS4, the human homolog of the mouse light-ear gene

Suzuki, Tamio; Li, Wei; Zhang, Qing; Karim, Amna; Novak, Edward K.; Sviderskaya, Elena V.; Hill, Simon P.; Bennett, Dorothy C.; Levin, Alex V.; Nieuwenhuis, H. Karel; Fong, Chin‐To; Castellan, Claudio; Miterski, Bianca; Swank, Richard T.; Spritz, Richard A.

doi:10.1038/ng835

Cited by 175 publications

(161 citation statements)

References 26 publications

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“…Mice have more than 16 different genes with HPS-like phenotypes (40), although many of the gene functions are unknown. At least six mouse models have the orthologous mutations to the human genes (41)(42)(43)(44)(45)(46). Interestingly, murine models of HPS-1 (Pale ear) and HPS-2 (Pearl) show activation of alveolar macrophages in the lung, but not in the blood or peritoneum (47,48).…”

Section: Murine Modelsmentioning

confidence: 99%

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

et al. 2016

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Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive genetic disorder characterized by oculocutaneous albinism and a bleeding diathesis due to platelet dysfunction. More than 50% of cases worldwide are diagnosed on the Caribbean island of Puerto Rico. Genetic testing plays a growing role in diagnosis; however, not all patients with HPS have identified genetic mutations. In Puerto Rico, patients with HPS are often identified shortly after birth by their albinism, although the degree of hypopigmentation is highly variable. Ten subtypes have been described. Patients with HPS-1, HPS-2, and HPS-4 tend to develop pulmonary fibrosis in Puerto Rico; 100% of patients with HPS-1 develop HPS-PF. HPS-PF and idiopathic pulmonary fibrosis are considered similar entities (albeit with distinct causes) because both can show similar histological disease patterns. However, in contrast to idiopathic pulmonary fibrosis, HPS-PF manifests much earlier, often at 30-40 years of age. The progression of HPS-PF is characterized by the development of dyspnea and increasingly debilitating hypoxemia. No therapeutic interventions are currently approved by the U.S. Food and Drug Administration for the treatment of HPS and HPS-PF. However, the approval of two new antifibrotic drugs, pirfenidone and nintedanib, has prompted new interest in identifying drugs capable of reversing or halting the progression of HPS-PF. Thus, lung transplantation remains the only potentially life-prolonging treatment. At present, two clinical trials are recruiting patients with HPS-PF to identify biomarkers for disease progression. Advances in the diagnosis and management of these patients will require the establishment of multidisciplinary centers of excellence staffed by experts in this disease.

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Section: Murine Modelsmentioning

confidence: 99%

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

et al. 2016

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“…In a few HPS cases in which the molecular consequences of disease-causing mutations have been studied, the mutations were found not only to affect the protein encoded by the mutant gene but also to lead to secondary destabilization and degradation of the corresponding protein complex [9]; a similar phenomenon was observed in mouse strains carrying mutations in the orthologs of each of the genes associated with HPS in humans [10,12,[14][15][16][17]. This has led to the notion that the different types of HPS could be classified into clinically relevant groups depending upon the affected protein complex [1].…”

Section: Introductionmentioning

confidence: 79%

“…The most prevalent type of HPS is HPS-1, which is due to mutations in a gene first identified through positional cloning of the genetic lesion shared by HPS patients from Northwestern Puerto Rico [7]. Other HPS genes were subsequently identified through positional cloning and/or candidate gene approaches [8][9][10][11][12][13]. Two characteristics are shared by all of these genes: (i) their expression in a wide variety of tissues and cell types, despite the main manifestations of HPS being a consequence of defects in cell-type-specific organelles, and (ii) the association of their products into one of four stable protein complexes, namely Adaptor Protein (AP)-3 (containing the product of the gene mutated in HPS-2), Biogenesis of Lysosome-related Organelles Complex (BLOC)-1 (containing the products of the genes mutated in HPS-7 and -8), BLOC-2 (containing the products of the genes mutated in HPS-3, -5 and -6) and BLOC-3 (containing the products of the genes mutated in HPS-1 and -4) ( Table 1) [1].…”

Section: Introductionmentioning

confidence: 99%

An immunoblotting assay to facilitate the molecular diagnosis of Hermansky–Pudlak syndrome

Nazarian

Huizing

Helip-Wooley

et al. 2008

Molecular Genetics and Metabolism

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Hermansky-Pudlak syndrome (HPS) comprises a constellation of human autosomal recessive disorders characterized by albinism and platelet storage pool deficiency. At least eight types of HPS have been defined based on the identity of the mutated gene. These genes encode components of four ubiquitously expressed protein complexes, named Adaptor Protein (AP)-3 and Biogenesis of Lysosome-related Organelles Complex (BLOC)-1 through -3. In patients of Puerto Rican origin, the molecular diagnosis can be based on analysis of two founder mutations. On the other hand, identification of the HPS type in other patients relies on the sequencing of all candidate genes. In this work, we have developed a biochemical assay to minimize the number of candidate genes to be sequenced per patient. The assay consists of immunoblotting analysis of extracts prepared from skin fibroblasts, using antibodies to one subunit per protein complex. The assay allowed us to determine which complex was defective in each of a group of HPS patients with unknown genetic lesions, thus subsequent sequencing was limited to genes encoding the corresponding subunits. Because no mutations within the two genes encoding BLOC-3 subunits could be found in two patients displaying reduced BLOC-3 levels, the possible existence of additional subunits was considered. Through sizeexclusion chromatography and sedimentation velocity analysis, the native molecular mass of BLOC-3 was estimated to be 140 ± 30 kDa, a value most consistent with the idea that BLOC-3 is a HPS1•HPS4 heterodimer (∼156 kDa) albeit not inconsistent with the putative existence of a relatively small third subunit.

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“…1). The fact that all genes currently implicated in the pathogenesis of HPS are expressed in a wide variety of cell types (11)(12)(13)(14)(15)(16) also supports the notion that their function may be more general than regulating the biogenesis of only melanosomes and platelet dense granules.…”

mentioning

confidence: 82%

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)

Starcevic¹,

Dell’Angelica

2004

Journal of Biological Chemistry

229

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Biogenesis of lysosome-related organelles complex-1 (BLOC-1) is a ubiquitously expressed multisubunit protein complex required for the normal biogenesis of specialized organelles of the endosomal-lysosomal system, such as melanosomes and platelet dense granules. The complex is known to contain the coiled-coil-forming proteins, Pallidin, Muted, Cappuccino, and Dysbindin. The genes encoding these proteins are defective in inbred mouse strains that serve as models of Hermansky-Pudlak syndrome (HPS), a genetic disorder characterized by hypopigmentation and platelet storage pool deficiency. In addition, mutation of human Dysbindin causes HPS type 7. Here, we report the identification of another four subunits of the complex. One is Snapin, a coiled-coilforming protein previously characterized as a binding partner of synaptosomal-associated proteins 25 and 23 and implicated in the regulation of membrane fusion events. The other three are previously uncharacterized proteins, which we named BLOC subunits 1, 2, and 3 (BLOS1, -2, and -3). Using specific antibodies to detect endogenous proteins from human and mouse cells, we found that Snapin, BLOS1, BLOS2, and BLOS3 co-immunoprecipitate, and co-fractionate upon size exclusion chromatography, with previously known BLOC-1 subunits. Furthermore, steady-state levels of the four proteins are significantly reduced in cells from pallid mice, which carry a mutation in Pallidin and display secondary loss of other BLOC-1 subunits. Yeast two-hybrid analyses suggest a network of binary interactions involving all of the previously known and newly identified subunits. Interestingly, the HPS mouse model strain, reduced pigmentation, carries a nonsense mutation in the gene encoding BLOS3. As judged from size exclusion chromatographic analyses, the reduced pigmentation mutation affects BLOC-1 assembly less severely than the pallid mutation. Mutations in the human genes encoding Snapin and the BLOS proteins could underlie novel forms of HPS.

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Hermansky-Pudlak syndrome is caused by mutations in HPS4, the human homolog of the mouse light-ear gene

Cited by 175 publications

References 26 publications

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

An immunoblotting assay to facilitate the molecular diagnosis of Hermansky–Pudlak syndrome

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)

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