Sandy: a new mouse model for platelet storage pool deficiency

Swank, Richard T.; Sweet, Hope O.; Davisson, Muriel T.; Reddington, Madonna; Novak, Edward K.

doi:10.1017/s0016672300029608

Cited by 65 publications

(44 citation statements)

References 40 publications

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“…Electron microscopy of mouse eyes (10), assays of platelet morphology and function (11), and assays of kidney and urine ␤-glucuronidase and ␤-galactosidase (12) were carried out as described. Platelet aggregation was determined by the impedance method in whole blood in response to 1 g͞ml collagen in bf͞bf and C57BL͞6J mice (11). ATP release was determined by luminescence methods.…”

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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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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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.

Self Cite

118

136

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“…We mated those F 1 progeny that contained BAC RP23-54F9 to sdy/sdy mice to produce F 2 progeny, which were typed by PCR techniques (primer sequences available on request) for the presence of the BAC transgene, the Dtnbp1 deletion and polymorphisms in microsatellite markers closely linked to Dtnbp1. We compared platelet serotonin concentrations 7 and coat colors in sdy/sdy F 2 progeny containing and lacking the BAC transgene. Dtnbp1 mRNA is smaller and dysbindin is undetectable in tissues of sdy mutant mice.…”

Section: Bac Rescue Of Sdy/sdy In Transgenic Micementioning

confidence: 99%

“…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 (42.73-43.29 Mb) between D13Mit244 and D13Mit267 (Fig.…”

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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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“…Blood was immediately drawn by heart puncture into 0.38% citrate, and platelets were isolated by differential centrifugation. 27 Mouse tissues were isolated from 6-to 10-week-old animals, washed with phosphate-buffered saline, and stored at Ϫ70°C for genomic DNA or protein preparation or immediately used for RNA isolation. …”

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confidence: 99%

The Slc35d3 gene, encoding an orphan nucleotide sugar transporter, regulates platelet-dense granules

Chintala

Tan

Gautam

et al. 2006

Blood

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Platelet dense granules are lysosomerelated organelles which contain high concentrations of several biologically important low-molecular-weight molecules. These include calcium, serotonin, adenine nucleotides, pyrophosphate, and polyphosphate, which are necessary for normal blood hemostasis. The synthesis of dense granules and other lysosomerelated organelles is defective in inherited diseases such as Hermansky-Pudlak syndrome (HPS) and Chediak-Higashi syndrome (CHS). HPS and CHS mutations in 8 human and at least 16 murine genes have been identified. Previous studies produced contradictory findings for the function of the murine ashen (Rab27a) gene in platelet-dense granules. We have used a positional cloning approach with one line of ashen mutants to establish that a new mutation in a second gene, Slc35d3, on mouse chromosome 10 is the basis of this discrepancy. IntroductionPlatelet activation induces secretion of the contents of several subcellular organelles, including ␣ granules, lysosomes, and dense granules. 1,2 ␣ Granules contain multiple proteins critical to adhesion and repair such as von Willebrand factor, thrombospondin, and fibrinogen. Lysosomes hold a battery of hydrolytic enzymes postulated to function in elimination of circulating platelet aggregates. Dense granules like lysosomes are acidic organelles but, unlike the aforementioned organelles, contain extremely high concentrations of small nonprotein components, including calcium, serotonin, adenine nucleotides, and pyrophosphate, which are thought to exist as an insoluble complex within platelets. 2 They are among the first components released from activated platelets and participate in clotting in numerous ways. For example, serotonin causes vasoconstriction. ADP activates and recruits nearby platelets. More recently, high concentrations of polyphosphate were found within platelet-dense granules. 3 Platelet-derived polyphosphate is a potent modulator of blood coagulation and fibrinolysis. 4 The biosynthesis of platelet dense and ␣ granules is thought to proceed through a common multivesicular body intermediate. 5 A wide variety of genes causative for the inherited diseases, Hermansky-Pudlak syndrome (HPS) and Chediak-Higashi syndrome (CHS), regulate the biosynthesis of dense granules, probably through control of vesicle trafficking. Platelet dense granules are absent or greatly reduced in a number in these diseases, and/or dense granule contents are significantly lower, leaving "empty" organelles. HPS is a genetically heterogeneous disease affecting the biosynthesis and/or intracellular transport of lysosome-related organelles (LROs) and their precursor vesicles. 6-10 LROs commonly affected include melanosomes, platelet-dense granules, and lamellar bodies of lung type II cells. Clinical presentation includes oculocutaneous albinism and lowered visual acuity, prolonged bleeding and, in many cases, early death from fibrotic lung disease. There is presently no permanent treatment for HPS, although bone marrow transplantation has restored normal p...

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Sandy: a new mouse model for platelet storage pool deficiency

Cited by 65 publications

References 40 publications

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

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

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

The Slc35d3 gene, encoding an orphan nucleotide sugar transporter, regulates platelet-dense granules

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