The beta3A subunit gene (Ap3b1) of the AP-3 adaptor complex is altered in the mouse hypopigmentation mutant pearl, a model for Hermansky- Pudlak syndrome and night blindness

Li, Feng; Seymour, Albert B.; Jiang, Shelley; To, Agnes; Peden, Andrew A.; Novak, Edward K.; Zhen, Lijie; Rusiniak, Michael E.; Eicher, Eva M.; Robinson, Margaret S.; Gorin, Michael B.; Swank, Richard T.

doi:10.1093/hmg/8.2.323

Cited by 238 publications

(168 citation statements)

References 30 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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“…Formation of lysosome-related organelles (LROs) has many mechanistic commonalities with that of conventional lysosomes, although with some molecular differences [53–55], and also requires the HOPS complex [18,53,56,57]. Mutations in Drosophila HOPS components disrupt the formation of the pigment granule, an insect LRO, leading to a loss of eye coloration [30,58–63].…”

Section: Resultsmentioning

confidence: 99%

Drosophila Rab2 controls endosome-lysosome fusion and LAMP delivery to late endosomes

2018

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Rab2 is a conserved Rab GTPase with a well-established role in secretory pathway function and phagocytosis. Here we demonstrate that Drosophila Rab2 is recruited to late endosomal membranes, where it controls the fusion of LAMP-containing biosynthetic carriers and lysosomes to late endosomes. In contrast, the lysosomal GTPase Gie/Arl8 is only required for late endosome-lysosome fusion, but not for the delivery of LAMP to the endocytic pathway. We also find that Rab2 is required for the fusion of autophagosomes to the endolysosomal pathway, but not for the biogenesis of lysosome-related organelles. Surprisingly, Rab2 does not rely on HOPS-mediated vesicular fusion for recruitment to late endosomal membranes. Our work suggests that Drosophila Rab2 is a central regulator of the endolysosomal and macroautophagic/autophagic pathways by controlling the major heterotypic fusion processes at the late endosome.

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“…Pearl mice have a mutation in the β subunit of the AP3 complex. Pearl mice have deficiencies/alterations in the localization and distribution of Zn 2+ , which can also be seen in mocha mutant mice, but pearl mice have normal hearing and balance (Balkema et al, 1983;Feng et al, 1999). This could be due to the subtlety of some vestibular defects, or may be because the pearl mutation alters some splice forms of the β3A protein, but not that expressed in neural tissue.…”

Section: Vesicular Trafficking Mutants Impact Several Points In Otocomentioning

confidence: 99%

Mixing model systems: Using zebrafish and mouse inner ear mutants and other organ systems to unravel the mystery of otoconial development

Hughes

Thalmann

et al. 2006

Brain Research

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Human vestibular dysfunction is an increasing clinical problem. Degeneration or displacement of otoconia is a significant etiology of age-related balance disorders and Benign Positional Vertigo (BPV). In addition, commonly used antibiotics, such as aminoglycoside antibiotics, can lead to disruption of otoconial structure and function. Despite such clinical significance, relatively little information has been compiled about the development and maintenance of otoconia in humans. Recent studies in model organisms and other mammalian organ systems have revealed some of the proteins and processes required for the normal biomineralization of otoconia and otoliths in the inner ear of vertebrates. Orchestration of extracellular biomineralization requires bringing together ionic and proteinaceous components in time and space. Coordination of these events requires the normal formation of the otocyst and sensory maculae, specific secretion and localization of extracellular matrix proteins, as well as tight regulation of the endolymph ionic environment. Disruption of any of these processes can lead to the formation of abnormally shaped, or ectopic, otoconia, or otoconial agenesis. We propose that normal generation of otoconia requires a complex temporal and spatial control of developmental and biochemical events. In this review, we suggest a new hypothetical model for normal otoconial and otolith formation based on matrix vesicle mineralization in bone which we believe to be supported by information from existing mutants, morphants, and biochemical studies.

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The beta3A subunit gene (Ap3b1) of the AP-3 adaptor complex is altered in the mouse hypopigmentation mutant pearl, a model for Hermansky- Pudlak syndrome and night blindness

Cited by 238 publications

References 30 publications

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

Drosophila Rab2 controls endosome-lysosome fusion and LAMP delivery to late endosomes

Mixing model systems: Using zebrafish and mouse inner ear mutants and other organ systems to unravel the mystery of otoconial development

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