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• W3093617355 abstract "HomeCirculation: Arrhythmia and ElectrophysiologyVol. 13, No. 10Expanding the Clinical Phenotype of Emerinopathies Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBExpanding the Clinical Phenotype of EmerinopathiesAtrial Standstill and Left Ventricular Noncompaction Michael H. GollobMD Michael H. GollobMichael H. Gollob Correspondence to: Michael H. Gollob, MD, Division of Cardiology, University of Toronto, 200 Elizabeth St, Rm 3GW-360, Toronto M5G 2C4, Ontario, Canada. Email E-mail Address: [email protected] Inherited Arrhythmia and Cardiomyopathy Program, Division of Cardiology, Department of Physiology, University of Toronto, ON, Canada. Search for more papers by this author Originally published20 Oct 2020https://doi.org/10.1161/CIRCEP.120.009338Circulation: Arrhythmia and Electrophysiology. 2020;13This article is a commentary on the followingCardiac EmerinopathyEMD (emerin) is a nuclear membrane protein and member of the nuclear lamina-associated protein family, which includes LMNA (lamin A). Together these proteins serve as the main structural framework of nuclei in mammalian cells. Among their many roles, they contribute to maintaining the structural integrity of myocytes, linking the nuclear lamina to the cellular cytoskeleton.1 Both EMD and LMNA are highly expressed in skeletal and cardiac muscle, and genetic defects in these genes are well-recognized causes of Emery-Dreifuss syndrome. This condition may be autosomal dominant in nature when caused by LMNA, or X-linked recessive in inheritance due to EMD mutations.See Article by Ishikawa et alEmery-Dreifuss syndrome is a rare form of muscular dystrophy most readily recognized first by joint deformities and contractures, muscle weakness, and wasting. In the commonest descriptions, cardiac involvement is a later manifestation and often results in sinus node disease, atrial fibrillation with progression to overt heart failure and ventricular arrhythmias. However, a description of primary cardiac electrical disease and cardiomyopathy preceding the manifestations of muscular dystrophy has also been reported.2EMD as a cause of an isolated cardiac phenotype in the absence of skeletal muscle disease, however, is a largely unrecognized condition.In this issue of the Circulation: Arrhythmia and Electrophysiology, in view of EMD genetic defects being associated with sinus node disease and progressive cardiac conduction disturbances, Ishikawa et al3 hypothesized that EMD might also be a cause of primary electrical disease in the absence of an associated skeletal muscle disorder. These investigators performed targeted DNA sequencing of EMD in 87 probands with evident sick sinus syndrome and conduction disease and discovered 3 patients harboring putative loss of function mutations within the EMD gene (initiation codon mutation, canonical splice site, and frameshift). Most interestingly, 2 of these probands had progressed to atrial standstill and had a history of stroke. Furthermore, all 3 probands demonstrated structural abnormalities consistent with left ventricular noncompaction (LVNC) and none demonstrated any evidence for neuromuscular disease. These observations represent the first reported association of isolated cardiac disease presenting with atrial standstill, stroke, and LVNC. To further explore the yield of EMD genetic defects in LVNC, the authors sequenced 102 LVNC patients and identified one other loss of function mutation (frameshift) in a 13-year-old male, who in addition to LVNC also had atrial arrhythmias and eventual atrial standstill.A Novel Genotype-Phenotype Association and the Genetics of Atrial StandstillIshikawa et al3 have succeeded in providing evidence for an expanded phenotype associated with EMD mutations, implicating emerin in a nonsyndromic cardiac disease of LVNC and atrial standstill. Karst et al4 previously reported on a loss of function EMD mutation associated with atrial fibrillation in a large family, also in the absence of neuromuscular disease, but did not describe the associated features of stroke, atrial standstill, or LVNC. Atrial standstill is a rare observation and has been reported secondary to genetic defects in other genes. Groenewegen et al5 reported on a large Dutch pedigree with familial atrial standstill and a mutation in the SCN5A gene (p. D1275N). We have identified this same mutation in a Canadian family with a history of atrial standstill, severe biatrial enlargement, and recurrent stroke (unpublished data). A mutation in MYL4, which encodes the atrial- specific mysoin essential light chain, has also recently been reported as a cause of early-onset familial atrial fibrillation and in association with atrial standstill.6 Common to all 3 now reported genetic forms of atrial standstill (EMD, SCN5A, and MYL4) is the inability to measure electrical signals from atrial tissue and the failure to electrically capture and contract atrial myocardium during electrophysiological study at advanced stages of disease. These observations reflect the severe atrial pathology induced by these genetic defects.A Common Pathway of Atrial Standstill: The T-Tubule and Excitation-Contraction CouplingThe transverse tubules (T-tubules) are invaginations of the cell membrane rich in several ion channels (eg, Nav1.5, L-type calcium channel) and other proteins committed to the critical task of excitation-contraction coupling in cardiac muscle cells. T-tubules reach the core of myocytes and ensure a tight coupling of excitation-contraction by closely apposing excitable channels and sarcomeric units, enabling a rapid binding of calcium and sarcomeric contraction following electrical depolarization.7 In relation to sarcomeric structure, T-tubules are located in regions referred to as Z-discs, where actin filaments anchor and ensure maintenance of T-tubule structure. A common binding partner to actin is both emerin and the atrial-specific essential light chain (MYL4), together playing a role in the integrity of the T-tubule and sarcomere interaction. Zebrafish expression of the atrial standstill associated MYL4 mutation, p.E11K, resulted in abolition of Z-disc structure in fish hearts and impairment of atrial chamber excitation-contraction. Loss of function mutations in EMD and MYL4 that effect their binding interaction with actin and impair Z-disc formation and T-tubule structure may explain the profound loss of excitation-contraction coupling seen in some patients harboring mutations in these genes. Sodium channel mutations that impart a unique effect of a depolarizing shift in channel activation kinetics, essentially creating a higher threshold for channel opening, may account for the presence of electrical standstill related to specific SCN5A variants.Precision Medicine for Atrial Standstill and LVNCThe study of Ishikawa et al3 has provided novel insights towards genotype-phenotype association in cardiovascular genetics. First, they demonstrate that putative loss of function mutations of EMD may be associated with LVNC and suggest this gene should be considered when this phenotype exists, particularly in association with atrial arrhythmias and atrial standstill. In addition, the rare phenotype of atrial standstill should trigger a consideration of 3 genes for primary genetic evaluation, now including SCN5A, MYL4, and EMD. Further studies to explore the pathophysiologic mechanisms of impaired myocardial excitation-contraction related to specific mutations within these genes should be encouraged.Sources of FundingNone.DisclosuresNone.FootnotesFor Sources of Funding and Disclosures, see page 1176.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to: Michael H. Gollob, MD, Division of Cardiology, University of Toronto, 200 Elizabeth St, Rm 3GW-360, Toronto M5G 2C4, Ontario, Canada. Email michael.[email protected]caReferences1. Holaska JM. Emerin and the nuclear lamina in muscle and cardiac disease.Circ Res. 2008; 103:16–23. doi: 10.1161/CIRCRESAHA.108.172197LinkGoogle Scholar2. Stoyanov N, Winterfield J, Varma N, Gollob MH. Atrial arrhythmias in the young: early onset atrial arrhythmias preceding a diagnosis of a primary muscular dystrophy.Europace. 2014; 16:1814–1820. doi: 10.1093/europace/euu141CrossrefMedlineGoogle Scholar3. Ishikawa T, Mishima H, Barc J, Takahashi MP, Hirono K, Terada S, Kowase S, Sato T, Mukai Y, Yui Y, et al.. Cardiac emerinopathy: a nonsyndromic nuclear envelopathy with increased risk of thromboembolic stroke due to progressive atrial standstill and left ventricular noncompaction.Circ Arrhythm Electrophysiol. 2020; 13:e008712. doi: 10.1161/CIRCEP.120.008712LinkGoogle Scholar4. Karst ML, Herron KJ, Olson TM. X-linked nonsyndromic sinus node dysfunction and atrial fibrillation caused by emerin mutation.J Cardiovasc Electrophysiol. 2008; 19:510–515. doi: 10.1111/j.1540-8167.2007.01081.xCrossrefMedlineGoogle Scholar5. Groenewegen WA, Firouzi M, Bezzina CR, Vliex S, van Langen IM, Sandkuijl L, Smits JP, Hulsbeek M, Rook MB, Jongsma HJ, et al.. A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill.Circ Res. 2003; 92:14–22. doi: 10.1161/01.res.0000050585.07097.d7LinkGoogle Scholar6. Orr N, Arnaout R, Gula LJ, Spears DA, Leong-Sit P, Li Q, Tarhuni W, Reischauer S, Chauhan VS, Borkovich M, et al.. A mutation in the atrial-specific myosin light chain gene (MYL4) causes familial atrial fibrillation.Nat Commun. 2016; 7:11303. doi: 10.1038/ncomms11303CrossrefMedlineGoogle Scholar7. Ibrahim M, Gorelik J, Yacoub MH, Terracciano CM. The structure and function of cardiac t-tubules in health and disease.Proc Biol Sci. 2011; 278:2714–2723. doi: 10.1098/rspb.2011.0624CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesCardiac EmerinopathyTaisuke Ishikawa, et al. Circulation: Arrhythmia and Electrophysiology. 2020;13 October 2020Vol 13, Issue 10Article InformationMetrics Download: 73 © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCEP.120.009338PMID: 33079577 Originally publishedOctober 20, 2020 Keywordsmuscular dystrophiesatrial standstillEditorialsemerincytoskeletonLVNCgeneticsPDF download SubjectsCerebrovascular Disease/StrokeGeneticsAtrial Fibrillation" @default.
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