Role of MRP4 (ABCC4) in Platelet Adenine Nucleotide-Storage

Jedlitschky, Gabriele; Cattaneo, Marco; Lubenow, Lena E.; Rosskopf, Dieter; Lecchi, Anna; Artoni, Andrea; Motta, Giovanna; Niessen, Juliane; Kroemer, Heyo K.; Greinacher, Andreas

doi:10.2353/ajpath.2010.090425

Cited by 41 publications

(5 citation statements)

References 22 publications

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“…Furthermore, MRP4 was suggested as the ADP transporter in DGs and two patients with δ-SPD-like phenotype (reduced adenine nucleotides but normal serotonin levels) show undetectable platelet MRP4 [22, 97, 122]. Nevertheless, no mutation in the MRP4 gene was found in these patients and direct evidence that MRP4 actually transports ADP is lacking.…”

Section: Cargos Of the Dense Granule Biogenesis Pathwaysmentioning

confidence: 99%

Storage pool diseases illuminate platelet dense granule biogenesis

Ambrosio

Pietro

2016

Platelets

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Platelet dense granules are membrane bound compartments that store polyphosphate and small molecules such as ADP, ATP, Ca2+ and serotonin. The release of dense granule contents plays a central role in platelet aggregation to form a hemostatic plug. Accordingly, congenital deficiencies in the biogenesis of platelet dense granules underlie human genetic disorders that cause storage pool disease and manifest with prolonged bleeding. Dense granules belong to a family of lysosome-related organelles, which also includes melanosomes, the compartments where the melanin pigments are synthesized. These organelles share several characteristics including an acidic lumen and, at least in part, the molecular machinery involved in their biogenesis. As a result, many genes affect both dense granule and melanosome biogenesis and the corresponding patients present not only with bleeding but also with oculocutaneous albinism. The identification and characterization of such genes has been instrumental in dissecting the pathways responsible for organelle biogenesis. Because the study of melanosome biogenesis has advanced more rapidly, this knowledge has been extrapolat ed to explain how dense granules are produced. However, some progress has recently been made in studying platelet dense granule biogenesis directly in megakaryocytes and megakaryocytoid cells. Dense granules originate from an endosomal intermediate compartment, the multivesicular body. Maturation and differentiation into a dense granule begins when newly synthesized dense granule specific proteins are delivered from early/recycling endosomal compartments. The machinery that orchestrates this vesicular trafficking is composed of a combination of both ubiquitous and cell type specific proteins. Here we review the current knowledge on dense granule biogenesis. In particular, we focus on the individual human and murine genes encoding the molecular machinery involved in this process and how their deficiencies result in disease.

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Section: Cargos Of the Dense Granule Biogenesis Pathwaysmentioning

confidence: 99%

Storage pool diseases illuminate platelet dense granule biogenesis

Ambrosio

Pietro

2016

Platelets

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“…ABCC4 encodes the ATP-binding cassette protein ABCC4, also known as multidrug resistance protein 4 (MRP4). Several studies indicated that ABCC4 is involved in the accumulation of the platelet-activating signaling molecule adenosine diphosphate (ADP) in platelet-dense granules ( Jedlitschky et al 2004( Jedlitschky et al , 2010. Our data suggest the noncoding SNP rs4148450 to be the functional variant at the 13q32.1 platelet To determine whether such overlap was expected by chance, we compared the number of overlapping SNPs with 100,000 random samples of 68 and 75 SNPs at the platelet (C ) and erythrocyte (D) QTLs, respectively.…”

Section: Identification Of Candidate Functional Variants At Platelet mentioning

confidence: 99%

Maps of open chromatin highlight cell type–restricted patterns of regulatory sequence variation at hematological trait loci

et al. 2013

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Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by metaanalyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell typespecific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits.

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“…Upon platelet activation and certain pathophysiological conditions, ABCC4 translocates to the plasma membrane and alters platelet function by increasing transport of several substrates 45 , 46 . In platelets, a rise in cyclic nucleotides prevents activation of signaling pathways.…”

Section: Resultsmentioning

confidence: 99%

“…Localization of ABCC4 in platelets has been debated and remains uncertain. ABCC4 was demonstrated to be highly expressed on the membrane of dense granules, which facilitates ADP accumulation and export 42 , 46 . It was also proposed that ABCC4 localization in platelets can be shifted from granules to the plasma membrane in certain high-risk conditions, including platelet activation 45 , 64 .…”

Section: Discussionmentioning

confidence: 99%