The mouse pale ear (
            <i>ep</i>
            ) mutation is the homologue of human Hermansky–Pudlak syndrome

Gardner, James A.; Wildenberg, Scott C.; Keiper, N M; Novak, Edward K.; Rusiniak, Michael E.; Swank, Richard T.; Puri, Neelu; Finger, Joshua N.; Hagiwara, Nobuko; Lehman, Anne L.; Gales, Tracy L.; Bayer, Manfred; King, Richard A.; Brilliant, Murray H.

doi:10.1073/pnas.94.17.9238

Cited by 135 publications

(114 citation statements)

References 39 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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“…Mutations in different genetic loci have been identified in patients with HPS 5,37 and in strains of animals demonstrating HPS-like storage pool defects such as pale-ear mice. 38 Although the relationships between the genetic defects and the molecular pathogenesis are not yet fully defined, the normal development of platelet-dense granules, which is related to lysosomal vesicle trafficking, is diminished, leading to reduced or absent platelet-dense granules. Our immunodetection of MRP4 in these granules (besides the plasma membrane and possibly other notidentified intracellular membranes) is supported by functional studies demonstrating ATP-dependent transport of 3 H-labeled cGMP, which paralleled MRP4 detection in subcellular fractionation ( Figure 1B).…”

Section: Discussionmentioning

confidence: 99%

The nucleotide transporter MRP4 (ABCC4) is highly expressed in human platelets and present in dense granules, indicating a role in mediator storage

Jedlitschky

Tirschmann

Lubenow

et al. 2004

Blood

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Platelet aggregation is initiated by the release of mediators as adenosine diphosphate (ADP) stored in platelet granules. Possible candidates for transport proteins mediating accumulation of these mediators in granules include multidrug resistance protein 4 (MRP4, ABCC4), a transport pump for cyclic nucleotides and nucleotide analogs. We investigated the expression of MRP4 in human platelets by immunoblotting, detecting a strong signal at 170 kDa. Immunofluorescence microscopy using 2 MRP4-specific antibodies revealed staining mainly in intracellular structures, which largely colocalized with the accumulation of mepacrine as marker for delta-granules and to a lower extent at the plasma membrane. IntroductionThe critical role played by platelets in hemostasis and thrombosis is related to their function as exocytotic cells that secrete effector molecules at the side of vascular injury. Platelets contain at least 3 types of intracellular granules, in which these mediators are stored and concentrated, known as alpha, dense, and lysosomal granules. 1 While alpha granules contain mainly polypeptides, as fibrinogen, von Willebrand factor, growth factors, and protease inhibitors, dense granules contain small molecules, specifically adenosine diphosphate (ADP), adenosine triphosphate (ATP), serotonin, and calcium. 2 Humans with defective dense granule exocytosis suffer from delta storage pool disease associated with a moderate bleeding tendency. The most severe delta storage pool disease is observed in Hermansky-Pudlak syndrome (HPS), a rare autosomal recessive disorder in which oculocutaneous albinism, bleeding, and lysosomal ceroid storage result from defects of melanosomes, platelet-dense granules, and lysosomes. [3][4][5] Little is known, however, about transport proteins mediating accumulation of the effector molecules in granules or their transport across the plasma membrane. Possible candidates include the multidrug resistance protein 4 (MRP4/ABCC4) and MRP5 (ABCC5). These belong to the C-branch of the human ATP-binding cassette (ABC) transporter superfamily, which consists of 12 members, 9 of which comprise the group of multidrug resistance proteins (MRP1-9; ABCC1-6 and ABCC10-12). 6,7 MRPs are integral membrane glycoproteins that mediate the primary active unidirectional export of organic anions from cells. Conjugates of lipophilic compounds with glutathione, glucuronate, and sulfate are preferred substrates of MRP1-3, [8][9][10] while cyclic purine nucleotides and nucleotide analogs have been identified as substrates for MRP4 and MRP5. 11-15 MRP5 mRNA has been detected in many tissues, 16,17 and the MRP5 protein could be localized in erythrocytes, 12 in smooth muscle cells of the genitourinary tract, 18 and in human heart cardiomyocytes, vascular endothelial, and smooth muscle cells. 19 MRP4 mRNA was detected in prostate, liver, testis, ovary, brain, kidney, and adrenal gland. 16,[20][21][22] Studies in membrane vesicles containing recombinant MRP4 indicate that it represents a transporter with a relatively br...

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“…We established a backcross between homozygous sdy mice and PWK wild-type mice (subspecies of Mus musculus musculus) as described 24 . sdy mutant mice have no obvious muscle abnormalities.…”

Section: Mice and Backcrossesmentioning

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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The mouse pale ear ( ep ) mutation is the homologue of human Hermansky–Pudlak syndrome

Cited by 135 publications

References 39 publications

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

The nucleotide transporter MRP4 (ABCC4) is highly expressed in human platelets and present in dense granules, indicating a role in mediator storage

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

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