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Nebulette Mutations in Cardiac Remodeling View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Journal of the American College of Cardiology Vol. 56, No. 18, 2010 © 2010 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2010.06.031 embryonic cardiomyocytes resulted in a loss of endoge- EDITORIAL COMMENT nous nebulette and a decrease in filament length (4,5), suggesting a role for nebulette in both thin filament and Z-disk assembly, function, and stability (3,5,6). Nebu- Nebulette Mutations lette interacts with a large number of thin filament- associated and Z-disk–associated proteins (3). The cen- in Cardiac Remodeling tral repeat domains associate with actin, troponin, and tropomyosin; the SH3 domain interacts with actin, Big Effects From ␣-actinin (7), CapZ, titin, myopalladin, zyxin (8), a Small Mechanosensor* desmin (9), and filamin C (10). In this issue of the Journal, Purevjav et al. (11) have Rashmi Ram, PHD, Burns C. Blaxall, PHD described de novo nebulette mutations in patients with DCM and endocardial fibroelastosis (EFE). The data in Rochester, New York part support the authors’ prior proposal that genes encoding cytoskeletal and sarcomeric proteins represent a major component of the “final common pathway” in the develop- Within the cytoskeletal framework of the heart, sarcomeres ment of heart failure (12). Previously, nebulette polymor- form the contractile machinery of cardiac muscle. Proteins phisms have been linked with nonfamilial DCM (13); this associated with the thick and thin filaments and the Z-disk study identifies 4 individual, de novo mutant variants of the participate in maintenance of the sarcomere structure. The human nebulette gene (1, K60N, had been previously Z-disks connect with integrins and dystroglycan of the reported in dbSNP; rs41277374). Two of the 4 mutations sarcolemma, allowing transmission of force generated by reside in the actin-binding domain (K60N, Q128R); the myofilaments to the adjacent sarcomeres, the extracellular other 2 are located within the nebulin-like repeat region matrix, and ultimately, to other cells. Additionally, proteins (G202R, A592E). Importantly, human cardiac disease phe- shuttling between sarcomeric and nonsarcomeric locales notypes were recapitulated in cardiac-targeted transgenic convey signals from the contractile machinery to the mouse models: cardiac expression of K60N or Q128R nucleus (1). These highly coordinated and overlapping mutations resulted in embryonic lethality, whereas the other functions of the cytoskeletal machinery enable rapid 2 (G202R, A592E) led to progressive DCM. This confir- adjustments in cardiac muscle to changes in physiological matory in vivo transgenic mouse data revealed distinct requirements. Mutations of several proteins associated cytoskeletal changes and myofibrillar organization resulting with sarcomere, Z-disk, and cytoskeletal assembly and from various nebulette mutations, and suggests roles of function cause dilated cardiomyopathy (DCM) and heart nebulette in early cardiac development. Finally, the effect of failure (2). Considering the important role of the Z-disk nebulette mutations on nebulette subcellular distribution in cardiac homeostasis, it is not surprising that mutations and the effect of cyclical mechanical stretch was assessed in in Z-disk proteins not only alter its physical connection embryonic rat cardiomyoblasts. with myofilaments and cytoskeletal proteins, but also In the present study (11), the authors identify multiple, affect the generation and transmission of mechanical and isolated mutations in a single nebulette gene, revealing biochemical signals. distinct Z-disk genotypes affiliated with distinct DCM phenotypes in both humans and transgenic mice. With See page 1493 the recent identification of numerous Z-disk mutations, genotype/phenotype analyses such as those outlined in Nebulette, the cardiac isoform of the giant (Ͼ600 kDa) the current study may help further identify, validate, actin-binding protein nebulin (found in skeletal muscle), is and/or stratify genetic subsets of DCM patients, possibly localized to, and predicted to extend Ͻ150 nm beyond, the extending the screening benefit to the patient’s immedi- Z-disk. Nebulette consists of a short N-terminal domain ate and extended families. The divergence in DCM and 22 nebulin-like repeats that are connected to a phenotype across the 4 identified nebulette mutations C-terminal SH3 domain by a short linker domain (3). (functionally validated in cardiac transgenic mice) reflects Overexpression of the linker or SH3 domains in chicken the multiple roles of nebulette in modulating cardiomy- ocyte stretch-strain with distinct structural/cytoskeletal modifications. *Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the Each region of nebulette appears to be critical for American College of Cardiology. myofibrillar assembly and stability. Functional mutations From the Aab Cardiovascular Research Institute, University of Rochester School of within the nebulin-like repeat region (such as of the G202R Medicine and Dentistry, Rochester, New York. Funding was provided by the National Institutes of Health (1R01 HL089885 and 3R01 HL089885). The authors and A592E mutations described by the authors) affect report they have no relationships with industry to disclose. maintenance and stabilization of the Z-disk assembly (14). 1504 Ram and Blaxall JACC Vol. 56, No. 18, 2010 Nebulette Mutations and Cardiomyopathy October 26, 2010:1503–5 Defective force generation and force transmission are widely ing, and structural functions of the Z-disk are independent proposed pathophysiological models of DCM (15). The or closely interrelated. cytoskeleton is a dynamic, adaptive structure that physically In summary, this exciting study by Purevjav et al. (11) links the contractile machinery to the extracellular matrix. identifies nebulette mutations associated with a continuum While changes in sarcomere/calcium handling proteins can of cardiomyopathy phenotypes and severities in humans. affect actin-myosin interactions (16) and force generation Importantly, the study validates the functional effects of the such as in the G202/Q128R mice, alterations in cytoskeletal newly identified nebulette mutants in vivo using cardiac proteins (A592E mice) reduce force transmission efficiency transgenic mice, revealing an array of pathologic cardiac (17). Given the unique properties of nebulette’s interaction phenotypes from neonate to adult. This finding suggests with both cytoskeletal and sarcomeric proteins across dif- that nebulette is required for normal genesis of the sarco- ferent domains, loss of coordinated interaction between the mere and stabilization of the Z-disk during both develop- sarcomere, cytoskeleton, and the sarcolemma may result in ment and adult cardiac contractility. Further, the study reduced cardiac contractile function, ultimately leading to identifies nebulette as an essential component of the stretch pathologic cardiac hypertrophy and cardiomyopathy. sensor machinery contributing to the pathophysiology of As previously described, the Z-disk, well recognized as a DCM and EFE, and opens the door to studying the roles of specialized stretch-interpreting sensor (18), enables the domain-specific Z-disk interactions affecting mechanical cardiomyocyte to sense increased mechanical load and and biochemical pathways for all cardiomyopathy pheno- respond with multiple changes, including altered gene types. expression, resulting in pathologic hypertrophy that decom- pensates into heart failure. Nebulette consistently associates Reprint requests and correspondence: Dr. Burns C. Blaxall, Aab with the Z-disk assembly, persisting from genesis of the Cardiovascular Research Institute, University of Rochester School myofibril of developing cardiac muscle (7) to its final of Medicine and Dentistry, 601 Elmwood Avenue, Box CVRI, position at the Z-disk in the mature heart. The authors (11) Rochester, New York 14642. E-mail: burns_blaxall@urmc. highlight that, during cyclic mechanical strain, nebulette rochester.edu. is initially localized to the perinuclear region, followed by its distribution along F-actin filaments reaching the cell periphery. In contrast, mutant nebulette proteins prefer- REFERENCES entially localized to the perinuclear region, with delayed 1. Gautel M. The sarcomere and the nucleus: functional links to expression of this mutant along maturing actin filaments. hypertrophy, atrophy and sarcopenia. Adv Exp Med Biol 2008;642: Further, in the Q128R mutants, nebulette appeared to be 176–91. dissociated from Z-disks, accompanied by a loss of 2. Jefferies JL, Towbin JA. Dilated cardiomyopathy. Lancet 2010;375: 752–62. desmin. 3. Moncman CL, Wang K. Functional dissection of nebulette demon- Calcineurin and NFAT are emerging candidate messen- strates actin binding of nebulin-like repeats and Z-line targeting of gers responsible for transmission of stretch signals from SH3 and linker domains. Cell Motil Cytoskeleton 1999;44:1–22. 4. Moncman CL, Wang K. Targeted disruption of nebulette protein Z-disks to the nucleus (18). Mechanical stretch can lead to expression alters cardiac myofibril assembly and function. Exp Cell Res activation of multiple stretch-activated kinase cascades, as 2002;273:204–18. well as changes in the activity of various ion channels/ 5. Moncman CL, Wang K. Nebulette: a 107 kD
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