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provided by Elsevier - Publisher Connector Journal of the American College of Cardiology Vol. 55, No. 11, 2010 © 2010 by the American College of Cardiology Foundation ISSN 0735-1097/10/$36.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2009.12.016

since been described (Table 1), of which some are currently EDITORIAL COMMENT available for clinical genetic testing for HCM and/or dilated cardiomyopathy (DCM). In this issue of the Journal, Chiu et al. (3) describe the Z-Disc in results of their study on a 23-member family of patients with predominantly HCM and features of atrial fibrillation, Hypertrophic Cardiomyopathy heart failure, and sudden death. However, some family members also showed signs less characteristic for HCM, Stretching the Cardiomyopathies?* such as right , possible arrhythmo- genic right ventricular cardiomyopathy (ARVC), and apical J. Martijn Bos, MD, PHD,† trabeculations. Linkage analysis identified a locus involving Michael J. Ackerman, MD, PHD†‡ 19 genes, of which 2—RYR2-encoded cardiac ryanodine receptor and ACTN2-encoded alpha-actinin-2—were se- Rochester, Minnesota lected for subsequent genetic analysis based on biological plausibility. This analysis elucidated the family’s HCM- causative mutation in ACTN2 with proper cosegregation of Hypertrophic cardiomyopathy (HCM) is a disease charac- mutation and disease phenotype. An ACTN2–HCM link terized by unexplained left ventricular hypertrophy. Occur- was further bolstered by the discovery of additional ACTN2 ring in about 1 in 500 individuals, HCM is the most mutations in an independent cohort of probands with common heritable cardiovascular disease, most often follow- HCM. ing an autosomal-dominant inheritance pattern with in- With the discovery of yet another Z-disc–associated complete penetrance and variable expressivity. Initially, HCM-susceptibility gene, a number of interesting ques- HCM was considered a disease of the sarcomere in lieu of tions surrounding the role of this myriad of in the the discovery of mutations involving the MYH7-encoded pathogenesis of HCM emerge. What is the role of muta- beta-myosin heavy chain and subsequently other neighbor- tions in Z-disc genes in the pathogenesis of HCM, and why ing sarcomeric proteins (1,2). Presently, clinical genetic does there seem to be such a large pleiotropic overlap, even testing for HCM includes the 9-gene panel for sarcomeric within families, with other cardiomyopathies, such as or myofilament HCM, which explains up to 65% of genetic DCM, ARVC, and even left ventricular noncompaction HCM in selected cohorts. With a large portion of HCM (LVNC)? Is there a specific Z-disc HCM phenotype, and genetically unexplained, genes encoding proteins involv- what other genes encoding the large cluster of proteins ing various functional or transcriptional processes of the composing the Z-disc will emerge as pathogenic substrates for heritable cardiomyopathies? See page 1127 First of all, it is striking that most HCM-susceptibility Z-disc genes are also associated with the pathogenesis of cardiomyocyte have been associated with disease pathogen- DCM, with both phenotypes sometimes seen in the same esis, particularly genes that encode the constellation of family (4–12). Of course, this pleiotropism has been noted proteins localizing to the cardiac Z-disc. The Z-disc com- previously for perturbations in the cardiac myofilaments, plex of proteins is located at either end of the contractile where mutations in cardiac actin were first reported to cause elements of the myofilament and is interconnected by the not only DCM but also HCM (5,13). Pathogenetically, for giant, sarcomere-stretching titin (encoded by TTN). the myofilaments, one can invoke domain-specific dysregu- Because of its close proximity to the contractile apparatus, lation whereby the particular cardiomyopathy (DCM vs. its specific structure–function relationship with regard to HCM) emerges depending on whether the mutation in a cyto-architecture, and its role as the stretch-sensor mecha- given myofilament gene disrupts a force-generating domain nism of the sarcomere, genes encoding these Z-disc proteins (HCM) or a force-transmitting domain (DCM) within the were hypothesized to be excellent candidate genes in the encoded protein (5,13). For Z-disc–mediated cardiomy- pathogenesis of HCM. Mutations in 7 Z-disc genes have opathies, however, it is more difficult to envision just how the 2 divergent, cardiomyopathic phenotypes emerge, especially because, given the Z-disc’s role as the sar- *Editorials published in the Journal of the American College of Cardiology reflect the comere’s stretch sensor and mechanoreceptor, maladap- views of the authors and do not necessarily represent the views of JACC or the tive dilation seems a more plausible phenotypic response American College of Cardiology. From the †Mayo Clinic Windland Smith Rice Sudden Death Genomics Labora- than maladaptive hypertrophy. tory, Rochester, Minnesota, and the ‡Departments of Medicine, Pediatrics, and Elucidating the specific phenotype or phenotypes of Molecular Pharmacology and Experimental Therapeutics/Divisions of Cardiovascular Z-disc HCM will help answer some of the intriguing Diseases and Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota. Dr. Acker- man is a consultant for Medtronic, St. Jude Medical, Boston Scientific, and questions surrounding this genetic subset of HCM. Initial PGxHealth, and has received royalties from PGxHealth. Z-disc genotype/HCM phenotype studies suggest that JACC Vol. 55, No. 11, 2010 Bos and Ackerman 1137 March 16, 2010:1136–8 Z-Disc HCM

SummaryGenes That of EncodeSummary HCM-Susceptibility Z-Disc of HCM-Susceptibility Proteins sinoatrial and atrioventricular nodal dysfunction, atrial Table 1 Genes That Encode Z-Disc Proteins standstill, and even left ventricular dysfunction and dilata- tion. Interestingly, their analysis narrowed in on the exact Gene Locus Protein Frequency (%) same locus as that found by Chiu et al. (3) ( ACTN2 1q42-q43 Alpha-actinin-2 Ͻ1 1q42-q43), but instead of point mutations in either RYR2 ANKRD1 10q23.33 Ankyrin repeat domain-1 Ͻ1 CSRP3 11p15.1 Muscle LIM protein Ͻ1 or ACTN2, large genomic deletions of RYR2 were discov- LBD3 10q22.2-q23.3 LIM binding domain-3 1–5 ered as causative for the disease in this family (21). (alias: ZASP) The finding by Chiu et al. (3) validates the role of MYOZ2 4q26-q27 Myozenin-2 Ͻ1 ACTN2 and Z-disc genes in the pathogenesis of HCM and TCAP 17q12-q21.1 Ͻ1 paves the way for future studies into the characteristics of VCL 10q22.1-q23 Vinculin/metavinculin Ͻ1 this interesting subset of genetic HCM. Not only does it

HCM ϭ hypertrophic cardiomyopathy. show the role of the Z-disc and ACTN2 in the development of a variety of cardiomyopathies, it also opens the door to Z-disc HCM is associated preferentially with a sigmoidal- study the role of the Z-discs and their interactions with shaped septal contour, whereas myofilament HCM shows cardiac ion channels, their associated diseases, and possibly preferentially a reverse septal curvature (14,15). However, even a final common pathway for all cardiomyopathies (22). individual cohort studies still lack the power to establish a particular Z-disc HCM phenotype. With more mutations Reprint requests and correspondence: Dr. J. Martijn Bos, Mayo being discovered in Z-disc genes in different cohorts, Clinic, Windland Smith Rice Sudden Death Genomics Labora- perhaps either a meta-analysis of the current literature or a tory, Guggenheim 5-11b, 200 First Street SW, Rochester, Min- collaborative effort between the different research groups nesota 55905. E-mail: [email protected]. might be able to shed light on this issue. Increasing the total number of patients with a mutation in 1 of the Z-disc genes could reveal a distinct Z-disc phenotype to help answer REFERENCES some of these questions. Is there a different age of onset of the disease compared with myofilament- or genotype- 1. Geisterfer-Lowrance AA, Kass S, Tanigawa G, et al. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin negative HCM? Are families indeed more likely to show heavy chain gene missense mutation. Cell 1990;62:999–1006. mixed HCM phenotypes of HCM and DCM, and possibly 2. Jarcho JA, McKenna W, Pare JA, et al. Mapping a gene for familial ARVC or LVNC? And are there any other features that hypertrophic cardiomyopathy to chromosome 14q1. N Engl J Med 1989;321:1372–8. make this genotypic subset different from the other? 3. Chiu C, Bagnall RD, Ingles J, et al. 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