Mutations in NEXN, a Z-Disc Gene, Are Associated with Hypertrophic Cardiomyopathy

Wang, Hu; Li, Zhaohui; Wang, Jizheng; Sun, Kai; Cui, Qiqiong; Song, Lei; Zou, Yubao; Wang, Xiaojian; Li, Xuan; Hui, Rutai; Fan, Yuxin

doi:10.1016/j.ajhg.2010.10.002

Cited by 80 publications

(54 citation statements)

References 32 publications

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“…Because of the epistatic relationship between laminin α 4 and ilk genes, mutations were screened in these genes from a cohort of patients with severe dilated cardiomyopathies and two mutations were subsequently identified in the laminin α 4 gene [143]. Similar to this candidate cardiomyopathy gene strategy, Nexilin, a highly enriched cardiac protein in the sarcomeric Z disk, was morpholino knocked down in the zebrafish to investigate its function [148, 149]. As a result, these nexilin morphants exhibited severely reduced cardiac contractile function, which led to the sequencing and identification of NEXILIN mutations in a registry of human dilated cardiomyopathy patients.…”

Section: Functional Heart Defectsmentioning

confidence: 99%

Zebrafish models in cardiac development and congenital heart birth defects

Neil

2012

Differentiation

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The zebrafish has become an ideal vertebrate animal system for investigating cardiac development due to its genetic tractability, external fertilization, early optical clarity and ability to survive without a functional cardiovascular system during development. In particular, recent advances in imaging techniques and the creation of zebrafish transgenics now permit the in vivo analysis of the dynamic cellular events that transpire during cardiac morphogenesis. As a result, the combination of these salient features provides detailed insight as to how specific genes may influence cardiac development at the cellular level. In this review, we will highlight how the zebrafish has been utilized to elucidate not only the underlying mechanisms of cardiac development and human congenital heart diseases (CHDs), but also potential pathways that may modulate cardiac regeneration. Thus, we have organized this review based on the major categories of CHDs – structural heart, functional heart, and vascular/great vessel defects, and will conclude with how the zebrafish may be further used to contribute to our understanding of specific human CHDs in the future.

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Section: Functional Heart Defectsmentioning

confidence: 99%

Zebrafish models in cardiac development and congenital heart birth defects

Neil

2012

Differentiation

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“…6 These include genes coding for proteins involved in intracellular calcium handling or constituting the Z-disc, the interface between the sarcomere and the cytoskeleton. 7,8 However, such genes are rarely tested by conventional techniques because of time and cost restraints. In such perspective, the novel possibilities offered by nextgeneration sequencing (NGS) seem particularly advantageous in genetically heterogeneous conditions such as HCM, in that they allow the rapid and affordable analysis truly exhaustive of the spectrum of disease-associated genes reported in the literature.…”

Section: Circ Cardiovasc Genetmentioning

confidence: 99%

Novel α-Actinin 2 Variant Associated With Familial Hypertrophic Cardiomyopathy and Juvenile Atrial Arrhythmias

Girolami

Iascone

Tomberli

et al. 2014

Circ Cardiovasc Genet

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Background— Next-generation sequencing might be particularly advantageous in genetically heterogeneous conditions, such as hypertrophic cardiomyopathy (HCM), in which a considerable proportion of patients remain undiagnosed after Sanger. In this study, we present an Italian family with atypical HCM in which a novel disease-causing variant in α-actinin 2 (ACTN2) was identified by next-generation sequencing. Methods and Results— A large family spanning 4 generations was examined, exhibiting an autosomal dominant cardiomyopathic trait comprising a variable spectrum of (1) midapical HCM with restrictive evolution with marked biatrial dilatation, (2) early-onset atrial fibrillation and atrioventricular block, and (3) left ventricular noncompaction. In the proband, 48 disease genes for HCM, selected on the basis of published reports, were analyzed by targeted resequencing with a customized enrichment system. After bioinformatics analysis, 4 likely pathogenic variants were identified: TTN c.21977G>A (p.Arg7326Gln); TTN c.8749A>C (p.Thr2917Pro); ACTN2 c.683T>C (p.Met228Thr); and OBSCN c.13475T>G (p.Leu4492Arg). The novel variant ACTN2 c.683T>C (p.Met228Thr), located in the actin-binding domain, proved to be the only mutation fully cosegregating with the cardiomyopathic trait in 18 additional family members (of whom 11 clinically affected). ACTN2 c.683T>C (p.Met228Thr) was absent in 570 alleles of healthy controls and in 1000 Genomes Project and was labeled as Damaging by in silico analysis using polymorphism phenotyping v2, as Deleterious by sorts intolerant from tolerant, and as Disease-Causing by Mutation Taster. Conclusions— A targeted next-generation sequencing approach allowed the identification of a novel ACTN2 variant associated with midapical HCM and juvenile onset of atrial fibrillation, emphasizing the potential of such approach in HCM diagnostic screening.

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“…More recently, our laboratory identified another disease gene, NEXN encoding nexilin, which is a crucial protein that functions to protect the cardiac Z-disc from damage that is caused by excessive strain [9]. However, each of these genes is associated with a very small minority of HCM cases.…”

Section: Genetic Causesmentioning

confidence: 99%

Progress in the Molecular Genetics of Hypertrophic Cardiomyopathy: A Mini-Review

Tian¹,

Liu²,

Zhou³

et al. 2013

Gerontology

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Background: Hypertrophic cardiomyopathy (HCM), which is characterized by unexplained and asymmetric left ventricular hypertrophy in the absence of other cardiac or systemic diseases, is an inherited cardiovascular disease and presents rising penetrance with aging. Objective: The purpose of this review is to offer an outline of recent progress in the molecular genetics of HCM and to discuss characteristics of elderly HCM patients. Methods: Studies were analyzed which included disease genes related to HCM, relationships between genotype and phenotype, potential pathogenesis of HCM, and the features of elderly patients with HCM. Results: HCM is caused by mutations in genes encoding myofilament proteins of the sarcomere, Z-disc proteins, Ca²⁺-handling proteins, and other proteins related to the sarcomere. Phenotypic manifestations of HCM are not just determined by these genes; modifying genes and epigenetic factors also contribute to the complexity of the HCM phenotype. The potential pathogenesis of HCM involves dominant negative function, an imbalance of myocardial energetic metabolism, and haploinsufficiency. Late-onset HCM presents its own features in the distribution of causal genes. Mutations in MYBPC3 may be the most common cause of delayed expression of HCM, and the sarcomere gene screen is most likely to be negative in elderly HCM patients. Conclusions: Despite progress in the identification of genetic causes and pathogenesis of HCM, there are still some questions that need to be better understood. It remains a great challenge to identify the cause of 50% of HCM cases in patients without an identified mutation. The application of a new genetic study technology may completely uncover the genetic background of these cases. In addition, the influences of causal mutations on the function and signaling of cardiocytes are expected to be elucidated further.

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Mutations in NEXN, a Z-Disc Gene, Are Associated with Hypertrophic Cardiomyopathy

Cited by 80 publications

References 32 publications

Zebrafish models in cardiac development and congenital heart birth defects

Zebrafish models in cardiac development and congenital heart birth defects

Novel α-Actinin 2 Variant Associated With Familial Hypertrophic Cardiomyopathy and Juvenile Atrial Arrhythmias

Progress in the Molecular Genetics of Hypertrophic Cardiomyopathy: A Mini-Review

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