The Gene Mutated in Cocoa Mice, Carrying a Defect of Organelle Biogenesis, Is a Homologue of the Human Hermansky–Pudlak Syndrome-3 Gene

Suzuki, Tamio; Li, Wei; Zhang, Qing; Novak, Edward K.; Sviderskaya, Elena V.; Wilson, Amanda J.; Bennett, Dorothy C.; Roe, Bruce A.; Swank, Richard T.; Spritz, Richard A.

doi:10.1006/geno.2001.6644

Cited by 81 publications

(75 citation statements)

References 33 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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“…Wild-type Melan-a (14) and Melan-bf (15) mouse melanocytes were cultured as described (10). Melan-bf cells were transfected with pIREShyg2-mVps33a, pIREShyg2-mVps33a bf , and pIREShyg2 by using FuGENE 6 transfection reagent (Roche Diagnostics, Basel), and stably transformed cell lines were selected in medium containing 300 g͞ml hygromycin B (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

The mouse organellar biogenesis mutant buff results from a mutation inVps33a, a homologue of yeastvps33andDrosophilacarnation

Suzuki

Oiso

Gautam

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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118

136

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In the mouse, more than 16 loci are associated with mutant phenotypes that include defective pigmentation, aberrant targeting of lysosomal enzymes, prolonged bleeding, and immunodeficiency, the result of defective biogenesis of cytoplasmic organelles: melanosomes, lysosomes, and various storage granules. Many of these mouse mutants are homologous to the human HermanskyPudlak syndrome (HPS), Chediak-Higashi syndrome, and Griscelli syndrome. We have mapped and positionally cloned one of these mouse loci, buff (bf), which has a mutant phenotype similar to that of human HPS. Mouse bf results from a mutation in Vps33a and thus is homologous to the yeast vacuolar protein-sorting mutant vps33 and Drosophila carnation (car). This is the first found defect of the class C vacuole͞prevacuole-associated target soluble Nethylmaleimide-sensitive factor attachment protein receptor (t-SNARE) complex in mammals and the first mammalian mutant found that is directly homologous to a vps mutation of yeast. VPS33A thus is a good candidate gene for a previously uncharacterized form of human HPS.H ermansky-Pudlak syndrome (HPS) is a disorder of organelle biogenesis in which oculocutaneous albinism, bleeding, and in most cases pulmonary fibrosis result from defects of melanosomes, platelet-dense granules, and lysosomes (1-4). Somewhat similar disorders, Chediak-Higashi and Griscelli syndromes, are additionally associated with severe immunodeficiency (2, 3). Important clues to the pathogenesis of these disorders have come from the mouse, in which Ͼ16 loci have been associated with mutant phenotypes similar to those of human HPS, Chediak-Higashi syndrome, and Griscelli syndrome (5, 6). Several of these genes have been identified recently and in a number of cases have been shown to result in homologous disorders in mice and humans (2-4). Although the functions of many of the corresponding gene products remain unknown, several are involved in various aspects of trafficking proteins to nascent organelles, particularly melanosomes, lysosomes, and cytoplasmic granules. In the yeast, Ͼ65 proteins have been implicated in biogenesis of the cytoplasmic vacuole, including the products of Ͼ40 vacuolar protein-sorting (vps) loci required for trafficking newly synthesized proteins from the late Golgi͞trans-Golgi network to the vacuole (7, 8). It seems likely that at least as many proteins are associated with organellar biogenesis in mammals.We have mapped and positionally cloned the mouse buff (bf ) locus, which is characterized by recessive coat-color hypopigmentation and mild platelet-storage pool deficiency but has little if any effect on lysosomal function. We find that mouse bf results from a missense substitution in Vps33a, a homologue of yeast vps33. The bf mutation results in defective melanosome morphology and melanogenesis both in vivo and in vitro. Expression of wild-type Vps33a in transfected mouse bf-mutant melanocytes complements this aberrant phenotype, whereas expression of bf-mutant Vps33a does not. These results establish murine bf a...

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“…BLOC-2, but Not AP-3, Acts Downstream of BLOC-1 in Tyrp1 Transport from Endosomes to Melanosomes BLOC-1 interacts physically with BLOC-2 and AP-3, and surface flux of Tyrp1 is increased in BLOC-2-and AP-3-deficient melanocytes (Di Pietro et al, 2006). To establish functional relationships between BLOC-1, BLOC-2, and AP-3 in Tyrp1 trafficking, intracellular Tyrp1 localization was assessed relative to various markers in BLOC-1-deficient melan-pa, BLOC-2-deficient melan-coa (lacking the HPS3 subunit; Suzuki et al, 2001;Gautam et al, 2004), and AP-3-deficient melan-pe cells (lacking the ␤3A subunit; Theos et al, 2005) derived from pallid, cocoa, and pearl mice, respectively. Unlike in BLOC-1-deficient cells, pigmented melanosomes are detectable in melan-coa and melan-pe by light microscopy (Supplemental Figure S4, a-d), although they are not as dense as in control cells.…”

Section: Bloc-1 Deficiency Likely Reduces Endocytic Rates Indirectly mentioning

confidence: 99%

“…Immortal melanocyte cell lines melan-mu1, -2, and -3 and melan-pa1, -2, and -3 were grown from skins of neonatal muted (Muted mu/mu ) Ink4a-ArfϪ/Ϫ B6.CHMU/Le and pallid Ink4a-ArfϪ/Ϫ mice, respectively, as described previously (Sviderskaya et al, 2002). Melan-mu3 (referred to as melan-mu), melan-rp2 (Gwynn et al, 2004) (referred to as melan-rp; Bloc1s3 rp/rp ), melanpa1 (referred to as melan-pa), melan-coa2 (Suzuki et al, 2001) (referred to as melan-coa; Hps3 coa/coa ), and melan-a (Bennett et al, 1987) were maintained as described previously (Sviderskaya et al, 2002). Retrovirus production from transiently transfected 293T cells and transduction of primary melanocytes and cell lines were carried out as described previously (Swift et al, 1999).…”

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confidence: 99%

BLOC-1 Is Required for Cargo-specific Sorting from Vacuolar Early Endosomes toward Lysosome-related Organelles

Setty

Tenza

Truschel

et al. 2007

MBoC

201

342

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Hermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by defects in the formation and function of lysosome-related organelles such as melanosomes. HPS in humans or mice is caused by mutations in any of 15 genes, five of which encode subunits of biogenesis of lysosome-related organelles complex (BLOC)-1, a protein complex with no known function.Here, we show that BLOC-1 functions in selective cargo exit from early endosomes toward melanosomes. BLOC-1-deficient melanocytes accumulate the melanosomal protein tyrosinase-related protein-1 (Tyrp1), but not other melanosomal proteins, in endosomal vacuoles and the cell surface due to failed biosynthetic transit from early endosomes to melanosomes and consequent increased endocytic flux. The defects are corrected by restoration of the missing BLOC-1 subunit. Melanocytes from HPS model mice lacking a different protein complex, BLOC-2, accumulate Tyrp1 in distinct downstream endosomal intermediates, suggesting that BLOC-1 and BLOC-2 act sequentially in the same pathway. By contrast, intracellular Tyrp1 is correctly targeted to melanosomes in melanocytes lacking another HPS-associated protein complex, adaptor protein (AP)-3. The results indicate that melanosome maturation requires at least two cargo transport pathways directly from early endosomes to melanosomes, one pathway mediated by AP-3 and one pathway mediated by BLOC-1 and BLOC-2, that are deficient in several forms of HPS. INTRODUCTIONHermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by hypopigmentation, prolonged bleeding, and sometimes ceroid accumulation, lung fibrosis, and/or immune defects leading to premature death Wei, 2006). HPS or a similar disorder in mice results from mutations in any of at least 15 genes (Wei, 2006). All of these genes are ubiquitously expressed, but their mutation in HPS affects mainly the generation and function of selected tissuespecific lysosome-related organelles (LROs;Bonifacino, 2004;Di Pietro and Dell'Angelica, 2005). Those LROs that are most severely affected in all forms of HPS-pigment cell melanosomes, platelet dense granules, and lung lamellar bodies-are unique in that they coexist with bona fide lysosomes in their respective cell types (Dell'Angelica et al., 2000;Marks and Seabra, 2001). The 15 known HPS-associated genes have been identified, and although the products of most are thought to participate in trafficking events that are uniquely required to form this class of LRO, the function of only a few is understood in detail.The genes disrupted in human HPS-7 (Li et al., 2003) and HPS-8 (Morgan et al., 2006) and in the mouse HPS models pallid, muted, reduced pigmentation (rp), cappuccino, and sandy encode five of the eight known subunits of a stable protein complex known as biogenesis of lysosome-related organelles complex (BLOC)-1 (Falcon-Perez et al., 2002;Moriyama and Bonifacino, 2002;Ciciotte et al., 2003;Li et al., 2003;Gwynn et al., 2004;Starcevic and Dell'Angelica, 2004). To date, no specific subcellular function has been assigned...

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The Gene Mutated in Cocoa Mice, Carrying a Defect of Organelle Biogenesis, Is a Homologue of the Human Hermansky–Pudlak Syndrome-3 Gene

Cited by 81 publications

References 33 publications

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

The mouse organellar biogenesis mutant buff results from a mutation inVps33a, a homologue of yeastvps33andDrosophilacarnation

BLOC-1 Is Required for Cargo-specific Sorting from Vacuolar Early Endosomes toward Lysosome-related Organelles

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