Reduced pigmentation (<i>rp</i>), a new coat colour gene with effects on kidney lysosomal glycosidases in the mouse

Gibb, Stuart L.; Håkansson, E. M.; Lundin, Lars-G.; Shire, J. G. M.

doi:10.1017/s0016672300020048

Cited by 20 publications

(20 citation statements)

References 28 publications

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“…33,46 Here, we extend the observations to demonstrate a marked decrease in the number of platelet dense bodies, the hallmark of HPS, with concomitant decrease in platelet serotonin levels. In addition, a detailed analysis of cultured rp/rp melanocytes revealed abnormalities characteristic of HPS, specifically decreased numbers of melanosomes with decreased pigment content and increased numbers of small and immature melanosomes.…”

Section: Discussionmentioning

confidence: 84%

“…HPS5/ru2, HPS6/ru, and HPS3/coa are components of BLOC-2, 16,29 whereas HPS1/ep interacts with HPS4/le in BLOC-3. 30,31 Interestingly, unlike AP-3, the known components of BLOC-1, -2, and -3 are confined to metazoans, suggesting they serve specialized functions in the biogenesis of those LROs (eg, platelet dense bodies, melanosomes) that are specific to higher eukaryotes.Of the known HPS mouse models, only subtle gray (sut) 32 and reduced pigmentation (rp) 33 have not been cloned. Here, we report the positional cloning of reduced pigmentation (GenBank accession no.…”

mentioning

confidence: 99%

“…The autosomal recessive rp mutation arose spontaneously on the C57BL/Tb (Tb) background in 1975. 33 The mutation was back-crossed to C57BL/ 10ScSn (B10) for 2 generations and subsequently maintained on the Tb and B10 mixed genetic background by rp/ϩ ϫ rp/rp matings. Heterozygotes, which show no phenotype, and closely related C57BL/6J (B6) mice served as normal controls in all studies.…”

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confidence: 99%

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Reduced pigmentation (rp), a mouse model of Hermansky-Pudlak syndrome, encodes a novel component of the BLOC-1 complex

Gwynn

Martina

Bonifacino

et al. 2004

Blood

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Hermansky-Pudlak syndrome (HPS), a disorder of organelle biogenesis, affects lysosomes, melanosomes, and platelet dense bodies. Seven genes cause HPS in humans (HPS1-HPS7 ) and at least 15 nonallelic mutations cause HPS in mice. Where their function is known, the HPS proteins participate in protein trafficking and vesicle docking/fusion events during organelle biogenesis. HPS-associated genes participate in at least 4 distinct protein complexes: the adaptor complex AP-3; biogenesis of lysosome-related organelles complex 1 (BLOC-1), consisting of 4 HPS proteins (pallidin, muted, cappuccino, HPS7/sandy); BLOC-2, consisting of HPS6/ruby-eye, HPS5/ruby-eye-2, and HPS3/cocoa; and BLOC-3, consisting of HPS1/pale ear and HPS4/light ear. Here, we report the cloning of the mouse HPS mutation reduced pigmentation (rp). We show that the wild-type rp gene encodes a novel, widely expressed 195-amino acid protein that shares 87% amino acid identity with its human orthologue and localizes to punctate cytoplasmic structures. IntroductionHermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder of organelle biogenesis that affects lysosomes and 2 lysosome-related organelles (LROs), melanosomes and platelet dense bodies. 1,2 HPS occurs in all ethnic groups but is particularly prevalent in northwest Puerto Rico (1/1800) due to a founder effect involving HPS1. 3 Melanosome defects led to oculocutaneous albinism causing nystagmus, decreased visual acuity, and skin damage on exposure to the sun. 4 Platelet dense body defects result in prolonged bleeding, which can be severe. Some patients develop progressive pulmonary fibrotic disease, which typically leads to death in the fourth to fifth decades. 4,5 The pathogenesis of lung fibrosis is poorly understood. It has been attributed to ceroid lipofuscin accumulation in defective lysosomes within alveolar macrophages. 6 Recent studies in mice suggest that a defect in a fourth LRO, lamellar bodies of type II pneumocytes, may contribute to lung disease in HPS. 7 HPS is clinically and genetically heterogeneous. Defects in 7 genes (HPS1-HPS7) cause HPS in humans. 8,9 Patients with HPS-1 and HPS-4 are at high risk for pulmonary involvement. 5,10 At least 15 nonallelic mutations cause HPS in mice, including the orthologues of HPS1-HPS7: pale ear (ep), pearl (pe), cocoa (coa), light ear (le), ruby-eye-2 (ru2), ruby-eye (ru), and sandy (sdy), respectively. 8,[11][12][13][14][15][16] Mutations at 6 loci in mice have been cloned for which no human HPS patients have yet been identified: mocha (mh), gunmetal (gm), buff (bf), pallid (pa), muted (mu), and cappuccino (cno). [17][18][19][20][21][22] Where their function is known, the HPS proteins participate in sorting of cargo proteins and vesicle targeting/fusion events during the biogenesis of LROs. Genes encoding the ␤3A (Ap3b1) and ␦ (Ap3d) subunits of the adaptor complex AP-3, which functions in endosomal-lysosomal protein trafficking, 23 are defective in HPS-2/ pearl and mocha, respectively. Buff is a defect in the gene encoding VPS33A, ...

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Section: Discussionmentioning

confidence: 84%

mentioning

confidence: 99%

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confidence: 99%

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Reduced pigmentation (rp), a mouse model of Hermansky-Pudlak syndrome, encodes a novel component of the BLOC-1 complex

Gwynn

Martina

Bonifacino

et al. 2004

Blood

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“…This gene location approximates the position of the spontaneous mouse mutation reduced pigmentation (rp) (34), in which pigment abnormalities and lysosomal dysfunction suggest an underlying defect in intracellular vesicle biogenesis (35). To determine if a mutation in the spectrin-like gene may be the cause of the rp defect, an informative subset of homozygous F2 rp animals from an intercross between C57Bl/6J-rp/rp and M. musculus castaneus (Cast/Ei) were analyzed for recombination between the rp locus and part of the spectrin-like gene detected with a clone N155-derived probe.…”

Section: Resultsmentioning

confidence: 99%

A New Spectrin, βIV, Has a Major Truncated Isoform That Associates with Promyelocytic Leukemia Protein Nuclear Bodies and the Nuclear Matrix

Tse

Tang

Jin

et al. 2001

Journal of Biological Chemistry

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We isolated cDNAs that encode a 77-kDa peptide similar to repeats 10 -16 of ␤-spectrins. Its gene localizes to human chromosome 19q13.13-q13.2 and mouse chromosome 7, at 7.5 centimorgans. A 289-kDa isoform, similar to full-length ␤-spectrins, was partially assembled from sequences in the human genomic DNA data base and completely cloned and sequenced. RNA transcripts are seen predominantly in the brain, and Western analysis shows a major peptide that migrates as a 72-kDa band. This new gene, spectrin ␤IV, thus encodes a full-length minor isoform (Sp␤IV⌺1) and a truncated major isoform (Sp␤IV⌺5). Immunostaining of cells shows a micropunctate pattern in the cytoplasm and nucleus. In mesenchymal stem cells, the staining concentrates at nuclear dots that stain positively for the promyelocytic leukemia protein (PML). Expression of Sp␤IV⌺5 fused to green fluorescence protein in cells produces nuclear dots that include all PML bodies, which double in number in transfected cells. Deletion analysis shows that partial repeats 10 and 16 of Sp␤IV⌺5 are necessary for nuclear dot formation. Immunostaining of whole-mount nuclear matrices reveals diffuse positivity with accentuation at PML bodies. Spectrin ␤IV is the first ␤-spectrin associated with a subnuclear structure and may be part of a nuclear scaffold to which gene regulatory machinery binds.Spectrin is an important component of the membrane skeleton attached to the inner leaf of the lipid bilayer of plasma membranes. First described in the erythrocyte (1), spectrins are found in all or almost all cells (2-4). In erythrocytes, an intact spectrin-based membrane skeleton is critical for the structural integrity of the plasma membrane. Defects in its components are associated with red cell fragility and premature destruction in the human diseases hereditary spherocytosis and elliptocytosis and their animal models (5). The function of a spectrin-based plasma membrane skeleton in non-erythroid tissues is less well defined, but it is hypothesized to be important in establishing and maintaining the asymmetric distribution of proteins in specialized plasma membrane domains, particularly in polarized cells (6).Recently, components of a spectrin-based membrane skeleton have also been found in several intracellular organelles. Isoforms of spectrin and ankyrin exist in Golgi membranes (7-9), lysosomal membranes (10), and secretory vesicles (11)(12)(13)(14). Spectrin also associates with actin-related protein 1 (centractin), a subunit of the dynactin complex, which associates with dynein and transports vesicles along microtubules in the secretory pathway (15). A spectrin-based membrane skeleton attached to intracellular organelles may provide a structural framework to anchor the vesicular transport machinery (16 -19). The potential role of a spectrin-based membrane skeleton in the nucleus is unclear. There are interesting recent reports indicating that spectrin ␣II is part of a nuclear protein complex involved in repair of DNA interstrand cross-links (20 -22). Whether ␣II-spectrin b...

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“…The other three are novel proteins herein referred to as BLOC subunits 1, 2 and 3 (BLOS1, BLOS2, and BLOS3). We also provide evidence that the mouse gene encoding BLOS3 is mutated in the HPS model strain, reduced pigmentation (rp) (33), for which the defective gene had not been identified.…”

Section: The Nucleotide Sequence(s) Reported In This Paper Has Been Smentioning

confidence: 99%

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

233

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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Reduced pigmentation (rp), a new coat colour gene with effects on kidney lysosomal glycosidases in the mouse

Cited by 20 publications

References 28 publications

Reduced pigmentation (rp), a mouse model of Hermansky-Pudlak syndrome, encodes a novel component of the BLOC-1 complex

Reduced pigmentation (rp), a mouse model of Hermansky-Pudlak syndrome, encodes a novel component of the BLOC-1 complex

A New Spectrin, βIV, Has a Major Truncated Isoform That Associates with Promyelocytic Leukemia Protein Nuclear Bodies and the Nuclear Matrix

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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