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ANK2
The Experts below are selected from a list of 1095 Experts worldwide ranked by ideXlab platform
Peter J Mohler – 1st expert on this subject based on the ideXlab platform
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a distal axonal cytoskeleton forms an intra axonal boundary that controls axon initial segment assembly
Cell, 2012Co-Authors: Mauricio R Galiano, Tammy Szuyu Ho, Chuansheng Zhang, Yasuhiro Ogawa, Kaejiun Chang, Michael C. Stankewich, Peter J Mohler, Matthew N. RasbandAbstract:Summary AnkyrinG (ankG) is highly enriched in neurons at axon initial segments (AISs) where it clusters Na + and K + channels and maintains neuronal polarity. How ankG becomes concentrated at the AIS is unknown. Here, we show that as neurons break symmetry, they assemble a distal axonal submembranous cytoskeleton, comprised of ankyrinB (ankB), αII-spectrin, and βII-spectrin, that defines a boundary limiting ankG to the proximal axon. Experimentally moving this boundary altered the length of ankG staining in the proximal axon, whereas disruption of the boundary through silencing of ankB, αII-spectrin, or βII-spectrin expression blocked AIS assembly and permitted ankG to redistribute throughout the distal axon. In support of an essential role for the distal cytoskeleton in ankG clustering, we also found that αII and βII-spectrin-deficient mice had disrupted AIS. Thus, the distal axonal cytoskeleton functions as an intra-axonal boundary restricting ankG to the AIS.
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Beyond membrane channelopathies: alternative mechanisms underlying complex human disease
Acta Pharmacologica Sinica, 2011Co-Authors: Konstantinos Dean Boudoulas, Peter J MohlerAbstract:Over the past fifteen years, our understanding of the molecular mechanisms underlying human disease has flourished in large part due to the discovery of gene mutations linked with membrane ion channels and transporters. In fact, ion channel defects (“channelopathies” — the focus of this review series) have been associated with a spectrum of serious human disease phenotypes including cystic fibrosis, cardiac arrhythmia, diabetes, skeletal muscle defects, and neurological disorders. However, we now know that human disease, particularly excitable cell disease, may be caused by defects in non-ion channel polypeptides including in cellular components residing well beneath the plasma membrane. For example, over the past few years, a new class of potentially fatal cardiac arrhythmias has been linked with cytoplasmic proteins that include sub-membrane adapters such as ankyrin-B ( ANK2 ), ankyrin-G ( ANK3 ), and alpha-1 syntrophin, membrane coat proteins including caveolin-3 ( CAV3 ), signaling platforms including yotiao ( AKAP9 ), and cardiac enzymes ( GPD1L ). The focus of this review is to detail the exciting role of lamins, yet another class of gene products that have provided elegant new insight into human disease.
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exon organization and novel alternative splicing of the human ANK2 gene implications for cardiac function and human cardiac disease
Journal of Molecular and Cellular Cardiology, 2008Co-Authors: Shane R Cunha, Solena Le Scouarnec, Jeanjacques Schott, Peter J MohlerAbstract:Abstract Recent findings illustrate a critical role for ankyrin-B function in normal cardiovascular physiology. Specifically, decreased expression of ankyrin-B in mice or human mutations in the ankyrin-B gene ( ANK2 ) results in potentially fatal cardiac arrhythmias. Despite the clear role of ankyrin-B in heart, the mechanisms underlying transcriptional regulation of ANK2 are unknown. In fact, to date there is no description of ANK2 genomic organization. The aims of this study were to provide a comprehensive description of the ANK2 gene and to evaluate the relative expression of alternative splicing events associated with ANK2 transcription in heart. Using reverse-transcriptase PCR on mRNA isolated from human hearts, we identify seven new exons associated with the ANK2 gene including an alternative first exon located ∼ 145 kb upstream of the previously-identified first exon. In addition, we identify over thirty alternative splicing events associated with ANK2 mRNA transcripts. Using real-time PCR and exon boundary-spanning primers to selectively amplify these splice variants, we demonstrate that these variants are expressed at varying levels in human heart. Finally, ankyrin-B immunoblot analysis demonstrates the expression of a heterogeneous population of ankyrin-B polypeptides in heart. ANK2 consists of 53 exons that span ∼ 560 kb on human chromosome 4. Additionally, our data demonstrates that ANK2 is subject to complex transcriptional regulation that likely results in differential ankyrin-B polypeptide function.
Solena Le Scouarnec – 2nd expert on this subject based on the ideXlab platform
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exon organization and novel alternative splicing of the human ANK2 gene implications for cardiac function and human cardiac disease
Journal of Molecular and Cellular Cardiology, 2008Co-Authors: Shane R Cunha, Solena Le Scouarnec, Jeanjacques Schott, Peter J MohlerAbstract:Abstract Recent findings illustrate a critical role for ankyrin-B function in normal cardiovascular physiology. Specifically, decreased expression of ankyrin-B in mice or human mutations in the ankyrin-B gene ( ANK2 ) results in potentially fatal cardiac arrhythmias. Despite the clear role of ankyrin-B in heart, the mechanisms underlying transcriptional regulation of ANK2 are unknown. In fact, to date there is no description of ANK2 genomic organization. The aims of this study were to provide a comprehensive description of the ANK2 gene and to evaluate the relative expression of alternative splicing events associated with ANK2 transcription in heart. Using reverse-transcriptase PCR on mRNA isolated from human hearts, we identify seven new exons associated with the ANK2 gene including an alternative first exon located ∼ 145 kb upstream of the previously-identified first exon. In addition, we identify over thirty alternative splicing events associated with ANK2 mRNA transcripts. Using real-time PCR and exon boundary-spanning primers to selectively amplify these splice variants, we demonstrate that these variants are expressed at varying levels in human heart. Finally, ankyrin-B immunoblot analysis demonstrates the expression of a heterogeneous population of ankyrin-B polypeptides in heart. ANK2 consists of 53 exons that span ∼ 560 kb on human chromosome 4. Additionally, our data demonstrates that ANK2 is subject to complex transcriptional regulation that likely results in differential ankyrin-B polypeptide function.
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dysfunction in ankyrin b dependent ion channel and transporter targeting causes human sinus node disease
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Solena Le Scouarnec, Naina Bhasin, Claude Vieyres, Thomas J Hund, Shane R Cunha, Olha M Koval, Celine Marionneau, Biyi Chen, Yuejin Wu, Sophie DemolombeAbstract:The identification of nearly a dozen ion channel genes involved in the genesis of human atrial and ventricular arrhythmias has been critical for the diagnosis and treatment of fatal cardiovascular diseases. In contrast, very little is known about the genetic and molecular mechanisms underlying human sinus node dysfunction (SND). Here, we report a genetic and molecular mechanism for human SND. We mapped two families with highly penetrant and severe SND to the human ANK2 (ankyrin-B/AnkB) locus. Mice heterozygous for AnkB phenocopy human SND displayed severe bradycardia and rate variability. AnkB is essential for normal membrane organization of sinoatrial node cell channels and transporters, and AnkB is required for physiological cardiac pacing. Finally, dysfunction in AnkB-based trafficking pathways causes abnormal sinoatrial node (SAN) electrical activity and SND. Together, our findings associate abnormal channel targeting with human SND and highlight the critical role of local membrane organization for sinoatrial node excitability.
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defining the cellular phenotype of ankyrin b syndrome variants human ANK2 variants associated with clinical phenotypes display a spectrum of activities in cardiomyocytes
Circulation, 2007Co-Authors: Peter J Mohler, Solena Le Scouarnec, I Denjoy, John S Lowe, Pascale Guicheney, Lise Caron, Iwona Driskell, Jeanjacques Schott, Kris Norris, A LeenhardtAbstract:Background— Mutations in the ankyrin-B gene (ANK2) cause type 4 long-QT syndrome and have been described in kindreds with other arrhythmias. The frequency of ANK2 variants in large populations and molecular mechanisms underlying the variability in the clinical phenotypes are not established. More importantly, there is no cellular explanation for the range of severity of cardiac phenotypes associated with specific ANK2 variants. Methods and Results— We performed a comprehensive screen of ANK2 in populations (control, congenital arrhythmia, drug-induced long-QT syndrome) of different ethnicities to discover unidentified ANK2 variants. We identified 7 novel nonsynonymous ANK2 variants; 4 displayed abnormal activity in cardiomyocytes. Including the 4 new variants, 9 human ANK2 loss-of-function variants have been identified. However, the clinical phenotypes associated with these variants vary strikingly, from no obvious phenotype to manifest long-QT syndrome and sudden death, suggesting that mutants confer a s…
Tyler R Webb – 3rd expert on this subject based on the ideXlab platform
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common human ANK2 variant confers in vivo arrhythmia phenotypes
Heart Rhythm, 2016Co-Authors: Nathaniel P Murphy, Hassan Musa, Tyler R Webb, Jerry Curran, John D HigginsAbstract:Background Human ANK2 (ankyrin-B) loss-of-function variants are directly linked with arrhythmia phenotypes. However, in atypical non–ion channel arrhythmia genes such as ANK2 that lack the same degree of robust structure/function and clinical data, it may be more difficult to assign variant disease risk based simply on variant location, minor allele frequency, and/or predictive structural algorithms. The human ankyrin-B p.L1622I variant found in arrhythmia probands displays significant diversity in minor allele frequency across populations. Objective The objective of this study was to directly test the in vivo impact of ankyrin-B p.L1622I on cardiac electrical phenotypes and arrhythmia risk using a new animal model. Methods We tested arrhythmia phenotypes in a new “knock-in” animal model harboring the human ankyrin-B p.L1622I variant. Results Ankyrin-B p.L1622I displays reduced posttranslational expression in vivo, resulting in reduced cardiac ankyrin-B expression and reduced association with binding-partner Na/Ca exchanger. Ankyrin-B L1622I/L1622I mice display changes in heart rate, atrioventricular and intraventricular conduction, and alterations in repolarization. Furthermore, ankyrin-B L1622I/L1622I mice display catecholamine-dependent arrhythmias. At the cellular level, ankyrin-B L1622I/L1622I myocytes display increased action potential duration and severe arrhythmogenic afterdepolarizations that provide a mechanistic rationale for the arrhythmias. Conclusion Our findings support in vivo arrhythmogenic phenotypes of an ANK2 variant with unusual frequency in select populations. On the basis of our findings and current clinical data, we support classification of p.L1622I as a “mild” loss-of-function variant that may confer arrhythmia susceptibility in the context of secondary risk factors including environment, medication, and/or additional genetic variation.