Evidence for Locus Heterogeneity in Puerto Ricans with Hermansky-Pudlak Syndrome

Hazelwood, Senator; Shotelersuk, Vorasuk; Wildenberg, Scott C.; Chen, David; Iwata, Fumino; Kaiser‐Kupfer, Muriel I.; White, James G.; King, Richard A.; Gahl, William A.

doi:10.1086/301611

Cited by 62 publications

(56 citation statements)

References 14 publications

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“…No curative therapies exist. HPS is a genetically heterogenous disease and is found in diverse populations worldwide (Hazelwood et al, 1997;Oh et al, 1998;Shotelersuk and Gahl, 1998;Spritz, 1999;Dell'Angelica et al, 1999). This is consistent with the existence of at least 14 genetically distinct mouse pigment mutants that exhibit phenotypes similar to those of HPS patients (Swank et al, 1998;Swank et al, in press).…”

Section: Introductionsupporting

confidence: 58%

Genomic Structure of the Mouse Ap3b1 Gene in Normal and Pearl Mice

Rigatti

Novak

et al. 2000

Genomics

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The mouse hypopigmentation mutant pearl is an established model for Hermansky-Pudlak syndrome (HPS), a genetically heterogenous disease with misregulation of the biogenesis/function of melanosomes, lysosomes, and platelet dense granules. The pearl (Ap3b1) gene encodes the ␤3A subunit of the AP-3 adaptor complex, which regulates vesicular trafficking. The genomic structure of the normal Ap3b1 gene includes 25 introns and a putative promoter sequence. The original pearl (pe) mutation, which has an unusually high reversion rate on certain strain backgrounds, has been postulated to be caused by insertion of a transposable element. Indeed, the mutation contains a 215-bp partial mouse transposon at the junction point of a large tandem genomic duplication of 6 exons and associated introns. At the cDNA level, three pearl mutations (pearl, pearl-8J, and pearl-9J) are caused by deletions or duplications of a complete exon(s).

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Section: Introductionsupporting

confidence: 58%

Genomic Structure of the Mouse Ap3b1 Gene in Normal and Pearl Mice

Rigatti

Novak

et al. 2000

Genomics

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“…This is based on the following observations: Immunoblotting ( Figure 1) and immunofluorescence microscopy ( Figures 2-4) showed the high abundance of MRP4 in platelets and its predominate localization in dense granules as indicated by colocalization with mepacrine, which is specifically concentrated in dense granules 35 (Figure 3), as well as by the altered distribution in platelets from a patient with Hermansky-Pudlak syndrome (HPS) (Figure 4). 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.…”

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

158

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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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“…Mild epistaxis was noted. The patient delivered four normal children without problems, but required a partial hysterectomy at age 41 treated with prednisone for 1 month at age 30, but barium studies of the upper and lower gastrointestinal tract were normal at age 35. The patient had no dyspnea, cough, or other pulmonary complaints.…”

Section: Clinical Findings In Hps-5mentioning

confidence: 99%

Cellular, Molecular and Clinical Characterization of Patients with Hermansky–Pudlak Syndrome Type 5

Huizing

Hess

Dorward

et al. 2004

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Hermansky-Pudlak syndrome (HPS) is a disorder of lysosome-related organelles such as melanosomes and platelet dense granules. Seven genes are now associated with HPS in humans. An accurate diagnosis of each HPS subtype has important prognostic and treatment implications. Here we describe the cellular, molecular, and clinical aspects of the recently identified HPS-5 subtype. We first analyzed the genomic organization and the RNA expression pattern of HPS5, located on chromosome 11p14, and demonstrated tissue-specific expression of at least three alternatively spliced HPS5 mRNA transcripts, coding for HPS5A and HPS5B proteins, that differ at their 5 0 -ends. Genetic screening of 15 unassigned HPS patients yielded six new HPS5 mutations in four patients. Clinically, our HPS-5 patients exhibited iris transillumination, variable hair and skin pigmentation, and absent platelet dense bodies, but not pulmonary fibrosis or granulomatous colitis. In two patients with homozygous missense mutations, hemizygosity was ruled out by gene-dosage multiplex polymerase chain reaction, and immunocytochemical analyses of their fibroblasts supported the HPS-5 diagnosis. Specifically, LAMP-3 distribution was restricted to the perinuclear region in HPS-5 fibroblasts, in contrast to the normal LAMP-3 distribution, which extended to the periphery. This specific intracellular vesicle distribution in fibroblasts, in combination with the clinical features, will improve the characterization of the HPS-5 subtype.

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Evidence for Locus Heterogeneity in Puerto Ricans with Hermansky-Pudlak Syndrome

Cited by 62 publications

References 14 publications

Genomic Structure of the Mouse Ap3b1 Gene in Normal and Pearl Mice

Genomic Structure of the Mouse Ap3b1 Gene in Normal and Pearl Mice

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

Cellular, Molecular and Clinical Characterization of Patients with Hermansky–Pudlak Syndrome Type 5

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