Hypertrophic cardiomyopathy mutations in the calponin-homology domain of ACTN2 affect actin binding and cardiomyocyte Z-disc incorporation

Haywood, Natalie; Wolny, Marcin; Rogers, Brendan; Trinh, Chi H.; Yu, Shizhu; Edwards, Thomas A.; Peckham, Michelle

doi:10.1042/bcj20160421

Cited by 45 publications

(69 citation statements)

References 41 publications

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“…The aactinin 2 protein is located at the Z-disk of the sarcomere in homodimers fulfilling three main functions: sarcomere formation, anchoring/crosslinking of actin thin filaments, and interaction with titin (Gautel & Djinovic-Carugo, 2016;Chopra et al, 2018). Several ACTN2 variants have been associated with HCM, but only a few could be validated as disease-causing with altered function (Theis et al, 2006;Chiu et al, 2010;Girolami et al, 2014;Haywood et al, 2016). One of these studies revealed reduced F-actin-binding affinity, altered Z-disk localization and dynamic behavior of two aactinin 2 mutants after gene transfer in CMs (Haywood et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Several ACTN2 variants have been associated with HCM, but only a few could be validated as disease-causing with altered function (Theis et al, 2006;Chiu et al, 2010;Girolami et al, 2014;Haywood et al, 2016). One of these studies revealed reduced F-actin-binding affinity, altered Z-disk localization and dynamic behavior of two aactinin 2 mutants after gene transfer in CMs (Haywood et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Disease modeling of a mutation in α‐actinin 2 guides clinical therapy in hypertrophic cardiomyopathy

et al. 2019

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Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease accompanied by structural and contractile alterations. We identified a rare c.740C>T (p.T247M) mutation in ACTN2, encoding α‐actinin 2 in a HCM patient, who presented with left ventricular hypertrophy, outflow tract obstruction, and atrial fibrillation. We generated patient‐derived human‐induced pluripotent stem cells (hiPSCs) and show that hiPSC‐derived cardiomyocytes and engineered heart tissues recapitulated several hallmarks of HCM, such as hypertrophy, myofibrillar disarray, hypercontractility, impaired relaxation, and higher myofilament Ca2+ sensitivity, and also prolonged action potential duration and enhanced L‐type Ca2+ current. The L‐type Ca2+ channel blocker diltiazem reduced force amplitude, relaxation, and action potential duration to a greater extent in HCM than in isogenic control. We translated our findings to patient care and showed that diltiazem application ameliorated the prolonged QTc interval in HCM‐affected son and sister of the index patient. These data provide evidence for this ACTN2 mutation to be disease‐causing in cardiomyocytes, guiding clinical therapy in this HCM family. This study may serve as a proof‐of‐principle for the use of hiPSC for personalized treatment of cardiomyopathies.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Disease modeling of a mutation in α‐actinin 2 guides clinical therapy in hypertrophic cardiomyopathy

et al. 2019

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“…Additional splicing of α-actinin-1 also produces smooth muscle and brain-specific isoforms [Kremerskothen et al, 2002; Waites et al, 1992]. In all cases, the α-actinin proteins are crucial in maintaining the architecture and stability of the cytoskeleton, and compromises in their structure can lead to impaired cell function and various pathologies [Kaplan et al, 2000; Mohapatra et al, 2003; Yao et al, 2004; Chiu et al, 2010; Girolami et al, 2014; Bagnall et al, 2014; Haywood et al, 2016; Kunishima et al, 2013; Gueguen et al, 2013; Yasutomi et al, 2016]. …”

Section: Introductionmentioning

confidence: 99%

Sarcomeric and nonmuscle α‐actinin isoforms exhibit differential dynamics at skeletal muscle Z‐lines

et al. 2018

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The α-actinin proteins are a highly conserved family of actin crosslinkers that mediate interactions between several cytoskeletal and sarcomeric proteins. Nonsarcomeric α-actinin-1 and α-actinin-4 crosslink actin filaments in the cytoskeleton, while sarcomeric α-actinin-2 and α-actinin-3 serve a crucial role in anchoring actin filaments to the muscle Z-line. To assess the difference in turnover dynamics and structure/function properties between the α-actinin isoforms at the sarcomeric Z-line, we used Fluorescence Recovery After Photobleaching (FRAP) in primary myofiber cultures. We found that the recovery kinetics of these proteins followed three distinct patterns: α-actinin-2/α-actinin-3 had the slowest turn over, α-actinin-1 recovered to an intermediate degree, and α-actinin-4 had the fastest recovery. Interestingly, the isoforms' patterns of recovery were reversed at adhesion plaques in fibroblasts. This disparity suggests that the different α-actinin isoforms have unique association kinetics in myofibers and that nonmuscle isoform interactions are more dynamic at the sarcomeric Z-line. Protein domain-specific investigations using α-actinin-2/4 chimeric proteins showed that differential dynamics between sarcomeric and nonmuscle isoforms are regulated by cooperative interactions between the N-terminal actin-binding domain, the spectrin-like linker region and the C-terminal calmodulin-like EF hand domain. Together, these findings demonstrate that α-actinin isoforms are unique in binding dynamics at the Z-line and suggest differentially evolved interactive and Z-line association capabilities of each functional domain.

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“…1 G). However, most ACTN2 mutations were identified in HCM [Chiu et al, 2010;Haywood et al, 2016], and less mutations have been detected in DCM patients [Mohapatra et al, 2003;Zimmerman et al, 2010;Gonzalez-Garay et al, 2013]. What is more, only 2 reports found that variants of ACTN2 can lead to overlap phenotypes of cardiomyopathy and arrhythmias [Bagnall et al, 2014;Girolami et al, 2014].…”

Section: Discussionmentioning

confidence: 99%

“…Alpha-actinin 2 (ACTN2) is the major component of the Z-disc in cardiac cells and there primarily functions in anchoring and crosslinking actin filaments at the lateral boundaries of the sarcomere [Haywood et al, 2016]. It also plays a critical role in the ion-channel organization [Ziane et al, 2010].…”

confidence: 99%

Whole-Exome Sequencing Identifies a Novel Mutation (p.L320R) of Alpha-Actinin 2 in a Chinese Family with Dilated Cardiomyopathy and Ventricular Tachycardia

Fan

Huang

Jin

et al. 2019

Cytogenet Genome Res

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Dilated cardiomyopathy (DCM) is a severe cardiovascular disease which can lead to heart failure and sudden cardiac death (SCD). The typical feature of DCM is left ventricular enlargement or dilatation. In some conditions, DCM and arrhythmia can occur concurrently, apparently promoting the prevalence of SCD. According to previous studies, mutations in more than 100 genes have been detected in DCM and/or arrhythmia patients. Here, we report a Chinese family with typical DCM, ventricular tachycardia, syncope, and SCD. Using whole-exome sequencing, a novel, likely pathogenic mutation (c.959T>G/p.L320R) of actinin alpha 2 (ACTN2) was identified in all affected family members. This novel mutation was also predicted to be disease-causing by MutationTaster, SIFT, and Polyphen-2. Our study not only expands the spectrum of ACTN2 mutations and contributes to the genetic diagnosis and counseling of the family, but also provides a new case with overlap phenotype that may be caused by the ACTN2 variant.

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Hypertrophic cardiomyopathy mutations in the calponin-homology domain of ACTN2 affect actin binding and cardiomyocyte Z-disc incorporation

Abstract: We have discovered that two mutations at the actin binding domain (ABD) of α-actinin-2 (ACTN2), which cause hypertrophic cardiomyopathy (HCM), have minor effects on its structure and ability to bind actin and integrate into Z-discs, providing a potential disease mechanism.

Cited by 45 publications

References 41 publications

Disease modeling of a mutation in α‐actinin 2 guides clinical therapy in hypertrophic cardiomyopathy

Disease modeling of a mutation in α‐actinin 2 guides clinical therapy in hypertrophic cardiomyopathy

Sarcomeric and nonmuscle α‐actinin isoforms exhibit differential dynamics at skeletal muscle Z‐lines

Whole-Exome Sequencing Identifies a Novel Mutation (p.L320R) of Alpha-Actinin 2 in a Chinese Family with Dilated Cardiomyopathy and Ventricular Tachycardia

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