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Peter J Mohler - One of the best experts 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, Kaejiun Chang, Peter J Mohler, Chuansheng Zhang, Michael C. Stankewich, Yasuhiro Ogawa, 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.
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common genetic variants in ANK2 modulate qt interval results from the kora study
Circulation-cardiovascular Genetics, 2008Co-Authors: Kamil Sedlacek, Shane R Cunha, Klaus Stark, Arne Pfeufer, Stefan Weber, Iris Berger, Siegfried Perz, Stefan Kaab, Hans Erich Wichmann, Peter J MohlerAbstract:Background—Spatial and timely variations in QT interval, even within its normal range, may underlie susceptibility to cardiac arrhythmias and sudden cardiac death. Given its important role in cardiac electrophysiology, we hypothesized that common genetic variation in ankyrin-B gene (ANK2) might modify QT interval length. Methods and Results—The study population consisted of 1188 participants of the World Health Organizational Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (WHO MONICA) general population survey Cooperative Health Research in the Region of Augsburg (KORA S3). Corrected QT interval was calculated using population specific linear regression formulas. A total of 22 single-nucleotide polymorphisms in the genomic region of ANK2 gene were genotyped using TaqMan technology. In a replication study, 6 single nucleotide polymorphisms were genotyped in 3890 individuals from a second population study (KORA S4). The rare variant of the single-nucleotide polymorphism rs6850768 (allele frequency, 0.28) significantly influenced duration of the QT interval, both in KORA S3 and KORA S4 populations. In homozygotes, the shortening of the QT interval was 3.79 ms (95% CI, 1.48 to 5.58; P0.001 and P0.0008 for log-additive and dominant model, respectively) in KORA S3 and 2.94 ms (95% CI, 1.11 to 4.77; P0.001 and P0.006 for log-additive and dominant genetic model, respectively) in KORA S4. A common 2-locus haplotype (rs11098171-rs6850768; population frequency, 28%) was associated with a QT interval difference of 2.85 ms (permutation; P0.006) in KORA S3 and 1.23 ms (permutation; P0.009) in KORA S4. Reverse transcription–polymerase chain reaction expression analysis of the human ANK2 5 genomic region in the human left ventricular tissue revealed 2 previously unidentified ANK2 5 exons in the proximity of the identified variants. Conclusions—Common genetic variants juxtaposed with novel exons in the distant 5 genomic region of ANK2 influence the QT interval length in the general population. These findings support the role of ankyrin-B in normal cardiac electric activity. (Circ Cardiovasc Genet. 2008;1:93-99.)
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Ankyrin-based targeting pathway regulates human sinoatrial node automaticity.
Channels, 2008Co-Authors: Thomas J Hund, Peter J MohlerAbstract:Cellular defects in ankyrin-based ion channels and transporter targeting pathways have previously been linked with abnormal vertebrate physiology and human disease. In a recent study, our group linked dysfunction in cardiac ankyrin-B function with human sinus node disease. Ankyrin-B deficient mice displayed bradycardia and heart rate variability similar to individuals harboring an ANK2 variant. Isolated sinoatrial node (SAN) cells from ankyrin-B-deficient animals displayed abnormal membrane expression of Na+/Ca2+ exchanger (NCX1), Na+/K+ ATPase (NKA), IP3 receptor (IP3R), and, surprisingly, Cav1.3. Loss of ankyrin-B promoted slow and irregular Ca2+ release, as well as afterdepolarizations in isolated SAN cardiomyocytes. Our findings suggest that ankyrin-B serves as a critical focal point for channels and transporters important for sarcoplasmic reticulum (SR) calcium homeostasis as well as membrane depolarization in SAN cells. The severity and penetrance of human ANK2 sinus node dysfunction likely reflects...
Solena Le Scouarnec - One of the best experts 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, Yuejin Wu, Biyi Chen, 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 - One of the best experts 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, Jerry Curran, John D Higgins, Tyler R WebbAbstract: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.
Vann Bennett - One of the best experts on this subject based on the ideXlab platform.
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ANK2 autism mutation targeting giant ankyrin b promotes axon branching and ectopic connectivity
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Rui Yang, Danwei Wu, Damaris N. Lorenzo, Alexandra Badea, Kathryn K Walderchristensen, Yonghui Jiang, William C Wetsel, Vann BennettAbstract:Giant ankyrin-B (ankB) is a neurospecific alternatively spliced variant of ANK2 , a high-confidence autism spectrum disorder (ASD) gene. We report that a mouse model for human ASD mutation of giant ankB exhibits increased axonal branching in cultured neurons with ectopic CNS axon connectivity, as well as with a transient increase in excitatory synapses during postnatal development. We elucidate a mechanism normally limiting axon branching, whereby giant ankB localizes to periodic axonal plasma membrane domains through L1 cell-adhesion molecule protein, where it couples microtubules to the plasma membrane and prevents microtubule entry into nascent axon branches. Giant ankB mutation or deficiency results in a dominantly inherited impairment in selected communicative and social behaviors combined with superior executive function. Thus, gain of axon branching due to giant ankB-deficiency/mutation is a candidate cellular mechanism to explain aberrant structural connectivity and penetrant behavioral consequences in mice as well as humans bearing ASD-related ANK2 mutations.
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cell autonomous adiposity through increased cell surface glut4 due to ankyrin b deficiency
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Damaris N. Lorenzo, Vann BennettAbstract:Abstract Obesity typically is linked to caloric imbalance as a result of overnutrition. Here we propose a cell-autonomous mechanism for adiposity as a result of persistent cell surface glucose transporter type 4 (GLUT4) in adipocytes resulting from impaired function of ankyrin-B (AnkB) in coupling GLUT4 to clathrin-mediated endocytosis. Adipose tissue-specific AnkB-KO mice develop obesity and progressive pancreatic islet dysfunction with age or high-fat diet (HFD). AnkB-deficient adipocytes exhibit increased lipid accumulation associated with increased glucose uptake and impaired endocytosis of GLUT4. AnkB binds directly to GLUT4 and clathrin and promotes their association in adipocytes. AnkB variants that fail to restore normal lipid accumulation and GLUT4 localization in adipocytes are present in 1.3% of European Americans and 8.4% of African Americans, and are candidates to contribute to obesity susceptibility in humans.
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Evolution in Action: Giant Ankyrins Awake
Developmental Cell, 2015Co-Authors: Vann Bennett, Kathryn K WalderAbstract:Reporting in Developmental Cell, Stephan et al. (2015) demonstrate critical axonal and presynaptic functions from acquisition of an enormous exon by the Drosophila ANK2 gene. They propose that highly elongated ANK2-XL molecules, associated with the plasma membrane through spectrin and ANK2-L, extend deep into the axoplasm to promote microtubule organization.
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Ankyrin-B Syndrome: Enhanced Cardiac Function Balanced by Risk of Cardiac Death and Premature Senescence
PLOS ONE, 2007Co-Authors: Peter J Mohler, Jane Healy, Annibale Alessandro Puca, Crystal F. Kline, R. Rand Allingham, Evangelia G. Kranias, Howard A. Rockman, Vann BennettAbstract:Here we report the unexpected finding that specific human ANK2 variants represent a new example of balanced human variants. The prevalence of certain ANK2 (encodes ankyrin-B) variants range from 2 percent of European individuals to 8 percent in individuals from West Africa. Ankyrin-B variants associated with severe human arrhythmia phenotypes (eg E1425G, V1516D, R1788W) were rare in the general population. Variants associated with less severe clinical and in vitro phenotypes were unexpectedly common. Studies with the ankyrin-B+/− mouse reveal both benefits of enhanced cardiac contractility, as well as costs in earlier senescence and reduced lifespan. Together these findings suggest a constellation of traits that we term “ankyrin-B syndrome”, which may contribute to both aging-related disorders and enhanced cardiac function.
A Leenhardt - One of the best experts on this subject based on the ideXlab platform.
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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...
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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, I Denjoy, John S Lowe, Pascale Guicheney, Lise Caron, Iwona Driskell, Jeanjacques Schott, Kris Norris, Solena Le Scouarnec, 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...