Alternative expression of platelet glycoprotein Ib(beta) mRNA from an adjacent 5' gene with an imperfect polyadenylation signal sequence.

Zieger, Barbara; Hashimoto, Yukihiko; Ware, Jerry

doi:10.1172/jci119188

Cited by 63 publications

(53 citation statements)

References 30 publications

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“…9,13 Figure 1 displays a diagrammatic representation of the 2 exons encoding platelet GP Ib␤ and also displays the close proximity of another gene, termed SEPT5 (previously designated CDCrel-1), whose 3Ј end is approximately 250 nucleotides 5Ј to exon 1 of the GP Ib␤ gene. 10,12,14 The close proximity of the 2 genes results in a transcriptionally complex locus owing to the presence of an aberrant polyadenylation signal sequence within the SEPT5 gene. 10 As a result of imperfect polyadenylation, a number of different transcripts have been described containing SEPT5, GP Ib␤, and SEPT5/GP Ib␤ mRNA sequences.…”

Section: Resultsmentioning

confidence: 99%

“…10,12,14 The close proximity of the 2 genes results in a transcriptionally complex locus owing to the presence of an aberrant polyadenylation signal sequence within the SEPT5 gene. 10 As a result of imperfect polyadenylation, a number of different transcripts have been described containing SEPT5, GP Ib␤, and SEPT5/GP Ib␤ mRNA sequences. 10 Both SEPT5 and GP Ib␤ transcripts and proteins have been identified in platelets, suggesting both genes may share regulatory elements that support megakaryocytic expression.…”

Section: Resultsmentioning

confidence: 99%

“…[10][11][12][13][14] To generate a targeting vector to ablate GP Ib␤ expression, a 4.4-kb HindIII/XhoI restriction fragment spanning exon 1 was subcloned into pBS/KS-( Figure 1A). The new plasmid was further modified to add a neomycin-resistance (neo r ) cassette at the XhoI restriction site and generate a single plasmid containing the 5Ј flanking arm and neo r cassette ( Figure 1B).…”

Section: Isolation Of the Mouse Gp Ib␤ Gene And Construction Of The Tmentioning

confidence: 99%

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Genetic deletion of mouse platelet glycoprotein Ibβ produces a Bernard-Soulier phenotype with increased α-granule size

Kato

Martínez

Russell

et al. 2004

Blood

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Here we report the characterization of a mouse model of the Bernard-Soulier syndrome generated by a targeted disruption of the gene encoding the glycoprotein (GP) Ib␤ subunit of the GP Ib-IX complex. Similar to a Bernard-Soulier model generated by disruption of the mouse GP Ib␣ subunit, GP Ib␤ Null mice display macrothrombocytopenia and a severe bleeding phenotype. When examined by transmission electron microscopy, the large platelets produced by a GP Ib␤ Null genotype revealed ␣-granules with increased size as compared with the ␣-granules from control mouse platelets. Data are presented linking the overexpression of a septin protein, SEPT5, to the presence of larger ␣-granules in the GP Ib␤ Null platelet. The SEPT5 gene resides approximately 250 nucleotides 5 to the GP Ib␤ gene and has been associated with modulating exocytosis from neurons and platelets as part of a presynaptic protein complex. Fusion mRNA transcripts present in megakaryocytes can contain both the SEPT5 and GP Ib␤ coding sequences as a result in an imperfect polyadenylation signal within the 3 end of both the human and mouse SEPT5 genes. We observed a 2-to 3-fold increase in SEPT5 protein levels in platelets from GP Ib␤ Null mice. These results implicate SEPT5 levels in the maintenance of normal ␣-granule size and may explain the variant granules associated with human GP Ib␤ mutations and the Bernard-Soulier syndrome.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Isolation Of the Mouse Gp Ib␤ Gene And Construction Of The Tmentioning

confidence: 99%

See 1 more Smart Citation

Genetic deletion of mouse platelet glycoprotein Ibβ produces a Bernard-Soulier phenotype with increased α-granule size

Kato

Martínez

Russell

et al. 2004

Blood

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“…Our studies evaluating the expression of a GP Ib-IX complex have supported this conclusion. 19,20,40,41 Although GP Ib-IX expression by osteoclasts has not been directly examined, it seems unlikely because by transcript profiling of cells undergoing osteoclastogenesis GP IX mRNA, a required subunit for surface expression of GP Ib␣, was not found. 42,43 Using immunofluorescence, we have been unable to identify expression of GP Ib-IX in osteoclasts (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Platelet Dysfunction and a High Bone Mass Phenotype in a Murine Model of Platelet-Type von Willebrand Disease

Suva

Hartman

Dilley

et al. 2008

The American Journal of Pathology

110

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The platelet glycoprotein Ib-IX receptor binds surfacebound von Willebrand factor and supports platelet adhesion to damaged vascular surfaces. A limited number of mutations within the glycoprotein Ib-IX complex have been described that permit a structurally altered receptor to interact with soluble von Willebrand factor, and this is the molecular basis of platelet-type von Willebrand disease. We have developed and characterized a mouse model of platelet-type von Willebrand disease (G233V) and have confirmed a platelet phenotype mimicking the human disorder. The mice have a dramatic increase in splenic megakaryocytes and splenomegaly. Recent studies have demonstrated that hematopoetic cells can influence the differentiation of osteogenic cells. Thus, we examined the skeletal phenotype of mice expressing the G233V variant complex. At 6 months of age, G233V mice exhibit a high bone mass phenotype with an approximate doubling of trabecular bone volume in both the tibia and femur. Serum measures of bone resorption were significantly decreased in G233V animals. With decreased bone resorption, cortical thickness was increased, medullary area decreased, and consequently, the mechanical strength of the femur was significantly increased. Using ex vivo bone marrow cultures, osteoclast-specific staining in the G233V mutant marrow was diminished, whereas osteoblastogenesis was unaffected. These studies provide new insights into the relationship between the regulation of megakaryocytopoiesis and bone mass. (Am J

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“…The C terminus of the fusion product contains all but the first seven amino acids of MSF. MSF is highly homologous to the genes of the septin family, including hCDC10 (46) and hCDCrel-1 (47,48) in human, and Nedd5 (38), Diff6, and H5 in the mouse. All of these genes completely conserve the GTP binding domain and are considered to be involved in cytokinesis.…”

Section: Discussionmentioning

confidence: 99%

MSF (MLL septin-like fusion), a fusion partner gene of MLL, in a therapy-related acute myeloid leukemia with a t(11;17)(q23;q25)

Osaka

Rowley

Zeleznik‐Le

1999

Proc. Natl. Acad. Sci. U.S.A.

163

150

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MLL (ALL1, Htrx, HRX), which is located on chromosome band 11q23, frequently is rearranged in patients with therapy-related acute myeloid leukemia who previously were treated with DNA topoisomerase II inhibitors. In this study, we have identified a fusion partner of MLL in a 10-year-old female who developed therapy-related acute myeloid leukemia 17 months after treatment for Hodgkin's disease. Leukemia cells of this patient had a t(11;17)(q23;q25), which involved MLL as demonstrated by Southern blot analysis. The partner gene was cloned from cDNA of the leukemia cells by use of a combination of adapter reverse transcriptase-PCR, rapid amplification of 5 cDNA ends, and BLAST database analysis to identify expressed sequence tags. The fulllength cDNA of 2.8 kb was found to be an additional member of the septin family, therefore it was named MSF (MLL septin-like fusion). Members of the septin family conserve the GTP binding domain, localize in the cytoplasm, and interact with cytoskeletal filaments. A major 4-kb transcript of MSF was expressed ubiquitously; a 1.7-kb transcript was found in most tissues. An additional 3-kb transcript was found only in hematopoietic tissues. By amplification with MLL exon 5 forward primer and reverse primers in MSF, the appropriately sized products were obtained. MSF is highly homologous to hCDCrel-1, which is a partner gene of MLL in leukemias with a t(11;22)(q23;q11.2). Further analysis of MSF may help to delineate the function of MLL partner genes in leukemia, particularly in therapy-related leukemia.

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Alternative expression of platelet glycoprotein Ib(beta) mRNA from an adjacent 5' gene with an imperfect polyadenylation signal sequence.

Cited by 63 publications

References 30 publications

Genetic deletion of mouse platelet glycoprotein Ibβ produces a Bernard-Soulier phenotype with increased α-granule size

Genetic deletion of mouse platelet glycoprotein Ibβ produces a Bernard-Soulier phenotype with increased α-granule size

Platelet Dysfunction and a High Bone Mass Phenotype in a Murine Model of Platelet-Type von Willebrand Disease

MSF (MLL septin-like fusion), a fusion partner gene of MLL, in a therapy-related acute myeloid leukemia with a t(11;17)(q23;q25)

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