The gene for the muted (mu) mouse, a model for Hermansky-Pudlak syndrome, defines a novel protein which regulates vesicle trafficking

Zhang, Q.

doi:10.1093/hmg/11.6.697

Cited by 71 publications

(66 citation statements)

References 32 publications

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“…The mu mutant mouse, which carries a spontaneous mutation on the Muted gene (Bloc1s5), abolishes the expression of the muted protein and affects the biogenesis of several LROs such as melanosomes and platelet-dense granules (Zhang et al, 2002). In our pilot study, we observed that mu mice had a different profile of morphological changes in LDCVs compared to sdy mice (Chen et al, 2008) or snapin-knockout mice (Pan et al, 2009;Tian et al, 2005).…”

Section: Introductionmentioning

confidence: 81%

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Impaired maturation of large dense-core vesicles in muted-deficient adrenal chromaffin cells

Hao

Wei

Feng

et al. 2015

Journal of Cell Science

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The large dense-core vesicle (LDCV), a type of lysosome-related organelle, is involved in the secretion of hormones and neuropeptides in specialized secretory cells. The granin family is a driving force in LDCV biogenesis, but the machinery for granin sorting to this biogenesis pathway is largely unknown. The mu mutant mouse, which carries a spontaneous null mutation on the Muted gene (also known as Bloc1s5), which encodes a subunit of the biogenesis of lysosome-related organelles complex-1 (BLOC-1), is a mouse model of Hermansky-Pudlak syndrome. Here, we found that LDCVs were enlarged in mu adrenal chromaffin cells. Chromogranin A (CgA, also known as CHGA) was increased in mu adrenals and mutedknockdown cells. The increased CgA in mu mice was likely due a failure to export this molecule out of immature LDCVs, which impairs LDCV maturation and docking. In mu chromaffin cells, the size of readily releasable pool and the vesicle release frequency were reduced. Our studies suggest that the muted protein is involved in the selective export of CgA during the biogenesis of LDCVs.

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Section: Introductionmentioning

confidence: 81%

“…The mu mutant mice and control CHMU/Le mice (wild-type, WT) were as described previously (Zhang et al, 2002). Other mouse mutants and their controls including pearl (pe) and buff (bf) in the C57BL/6J (B6) background, sandy (sdy) in the DBA/2J (DBA) background were are summarized Li et al (Li et al, 2004).…”

Section: Micementioning

confidence: 99%

Impaired maturation of large dense-core vesicles in muted-deficient adrenal chromaffin cells

Hao

Wei

Feng

et al. 2015

Journal of Cell Science

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“…We fixed eye tissues for 18 h at 4 °C in 3% glutaraldehyde and 0.1 M phosphate buffer, pH 7.2, and embedded and stained them with uranyl acetate and lead citrate 20 .…”

Section: Electron Microscopymentioning

confidence: 99%

Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1)

et al. 2003

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Hermansky-Pudlak syndrome (HPS; MIM 203300) is a genetically heterogeneous disorder characterized by oculocutaneous albinism, prolonged bleeding and pulmonary fibrosis due to abnormal vesicle trafficking to lysosomes and related organelles, such as melanosomes and platelet dense granules [1][2][3] . In mice, at least 16 loci are associated with HPS 4-6 , including sandy (sdy ; ref. 7 ). Here we show that the sdy mutant mouse expresses no dysbindin protein owing to a deletion in the gene Dtnbp1 (encoding dysbindin) and that mutation of the human ortholog DTNBP1 causes a novel form of HPS called HPS-7. Dysbindin is a ubiquitously expressed protein that binds to α-and β-dystrobrevins, components of the dystrophin-associated protein complex (DPC) in both muscle and nonmuscle cells 8 . We also show that dysbindin is a component of the biogenesis of lysosome-related organelles complex 1 ), which regulates Correspondence should be addressed to R.T.S (richard.swank@roswellpark.org). 11 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Genetics website. Competing Interests Statement:The authors declare that they have no competing financial interests. We previously showed 7 that the sdy mutant mouse is a valid model for human HPS and localized the gene sdy to mouse chromosome 13. Here we genotyped 20 microsatellite markers in 1,250 progeny of sdy backcrosses to localize sdy to the 2.2-cM interval between D13Mit244 and D13Mit267 (Fig. 1). We identified the sdy interval within a 28-Mb scaffold (Celera Discovery System) containing two known genes, Jmj and Dtnbp1 (Fig. 1b). We used PCR products of D13Mit179 and the Dtnbp1 cDNA as probes to generate a BAC contig covering the sdy interval (Fig. 1b). NIH Public AccessNorthern-blot analysis and sequencing of RT-PCR products of Jmj identified no abnormalities in sdy mutants, but truncated genomic PCR products (Fig. 2a) and mRNA ( Fig. 2b) of Dtnbp1 were apparent in sdy tissues. Sequencing of RT-PCR products showed that exons 6 and 7 (156 bp) of Dtnbp1 were deleted in mutant mice, resulting in the loss of 52 amino acids from position 119-172 of the dysbindin protein ( Supplementary Fig. 1 online). Genomic sequencing showed that this results from a large deletion (38,129 bp) from nucleotide 3,701 of intron 5 to nucleotide 12,377 of intron 7. This deletion was not found in twelve other inbred mouse strains (Fig. 2a), including coisogenic DBA/2J, indicating that it was not a strain-specific polymorphism. This in-frame deletion creates a 1.5-kb mutant dysbindin transcript ( Fig. 2b) and abolishes expression of the 51-kDa dysbindin 8 protein in sdy/sdy mice ( Fig. 2c). Expression of dysbindin is restored in sdy/sdy transgenic mice containing BAC54F9 (Fig. 2c). Platelet serotonin levels of six of these transgenics were normal (>1.12 μg per 10 9 platelets), whereas all five sdy/sdy litter-mates without BAC54F9 had platelet serotonin levels of <0.06 μg per 10 9 platelets. sdy/sdy progeny containing the BAC transgene had dar...

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“…At the very least, the eight genes already associated with the human disease (i.e., HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1 and BLOC1S3) should be included. It can also be argued that other genes encoding subunits of AP-3 or a BLOC should be taken into consideration as well, especially those for which mutations in the mouse counterpart have been shown to result in HPS-like phenotypes [34][35][36][37], thus potentially raising the number of candidate genes to eighteen (Table 1). On the other hand, one might consider excluding AP3S1 and AP3S2 from the list on the basis of an argument of genetic redundancy (i.e., both genes encode alternative AP-3 subunits with apparently the same molecular function [38]) or AP3D1 on the basis of the occurrence in Ap3d1-null mice of neurological phenotypes not yet observed in HPS patients [34].…”

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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The gene for the muted (mu) mouse, a model for Hermansky-Pudlak syndrome, defines a novel protein which regulates vesicle trafficking

Cited by 71 publications

References 32 publications

Impaired maturation of large dense-core vesicles in muted-deficient adrenal chromaffin cells

Impaired maturation of large dense-core vesicles in muted-deficient adrenal chromaffin cells

Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1)

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

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