EDITORIAL COMMENT
Phenotypic Heterogeneity of Sarcomeric Gene MutationsA Matter of Gain and Loss?*
Luisa Mestroni, MD*
University of Colorado Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado; and Cluster in BioMedicine, Trieste, Italy
* Reprint requests and correspondence: Dr. Luisa Mestroni, Molecular Genetics, CUCVI, 12700 East 19th Avenue, Mail Stop F442, Aurora, Colorado 80045-6511 (Email: Luisa.Mestroni{at}ucdenver.edu).
Key Words: hypertrophic cardiomyopathy • mutation • CARP • titin/connectin • dilated cardiomyopathy • ANKRD1
After several decades of intense research and various attempts at definition and classification, cardiomyopathies still remain disorders of remarkable and intriguing complexity. Once more, this aspect is elicited by the recent discovery that mutations in the cardiac ankyrin repeat protein (CARP), a protein functionally part of the sarcomere, can cause different types of cardiomyopathies, as reported by Moulik et al. (1) and Arimura et al. (2) in this issue of the Journal, as well as congenital heart disease (3).
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ANKRD1 in normal heart and disease
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CARP is a 36 kD protein encoded by the cardiac ankyrin repeat domain 1 gene ANKRD1, which maps on chromosome 10. ANKRD1 is a member of a conserved gene family, coding for muscle ankyrin repeat proteins (MARPs), involved in muscle stress response such as stretch, injury, and hypertrophy (4). CARP is a nuclear transcription cofactor, a signaling molecule predominantly expressed in the heart. CARP is found in the sarcomere, where it colocalizes with the N2A domain of titin and myopalladin in the I-band of the Z disk (Fig. 1), and in the nucleus (4). The expression of CARP is controlled, at least in part, by the titin-based mechanotransduction signaling pathway, and it is increased in heart development and conditions of injury and stress. In heart development, CARP acts as a transcriptional repressor of myocyte contractile elements. In heart failure, CARP is overexpressed, suggesting a role in the "fetal gene program" characteristic of the molecular remodeling of the failing heart (5).
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Figure 1 Model for the Titin-N2A Signaling Complex
The sequence of N2A titin interacts with muscle ankyrin repeat proteins (MARPs) such as cardiac ankyrin repeat protein (CARP), ANKRD2, or diabetes-related ankyrin repeat protein. Myopalladin associates with the MARP/N2A complex by interacting with the N-terminal domains of MARPs. CAPN3 = calpain 3; Ig = immunoglobulin; IS = muscle specific sequence; NH2 = N-terminal domain; PEVK = sequence element rich in proline (P), glutamic acid (E), lysine (K), and valine (V) residues. Reprinted with permission from Miller et al. (4).
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Because titin was previously found to be associated with both hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) (6–8), CARP, as part of the titin complex, was also hypothesized to play a role in cardiomyopathies. In this issue of the Journal, 2 reports (1,2) confirm this hypothesis and show that in fact ANKRD1 mutations can cause both DCM and HCM.
Arimura et al. (2) report the results of the ANKRD1 mutation screening in a large HCM population collected in Japan and in the U.S. In 384 index patients, they found 3 missense mutations (ANKRD1 Pro52Ala, Thr123Met, and Ile280Val), accounting for  1% of HCM cases. Interestingly, they also investigated the N2A CARP-binding domain of titin, and found 2 additional mutations (TTN Arg8500 and Arg8604Gln) in their HCM cohort. Moulik et al. (1) investigated a series of 208 DCM index patients of Japanese and U.S. origin, and found 3 missense mutations (ANKRD1 Pro105Ser, which was recurrent in 2 families, Val107Leu, and Met1841Ile) accounting for 2% of DCM cases, further supporting a role of the titin mechanotransduction complex in the pathogenesis of cardiomyopathies. But how to explain 2 different cardiomyopathies with opposite pathophysiology caused by the same gene?
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Phenotypic heterogeneity in cardiomyopathies
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Phenotypic heterogeneity (also called "allelic variants" in OMIM) (9) is a well-known and common phenomenon in genetics, referring to the occurrence of more than 1 phenotype caused by allelic mutations at a single locus (10); examples familiar to cardiologists are Duchenne and Becher muscular dystrophies caused by the same dystrophin gene, laminopathies ranging from progeria to lipodystrophy due to lamin A/C gene, and LQT syndrome and congenital conduction defect caused by the cardiac sodium channel gene SCN5A.
The reason for the clinical variability in allelic disorders lies in the different function of the mutant proteins. In the case of sarcomeric genes, it appears that a "gain" of function usually results in increased energy demand, inefficient adenosine triphosphate utilization, and hypertrophy, whereas a "loss" of function results in decreased contractility (Table 1). The 2 studies published in this issue seem to follow the rule. Arimura et al. (2) show that ANKRD1 mutations in HCM increase binding of CARP to titin and myopalladin, and that titin mutations at the CARP-binding site have the same effect. Conversely, Moulik et al. (1) show that ANKRD1 mutations in DCM cause a loss of CARP binding to talin 1, potentially leading to loss of stretch-sensing, disruption of the link between titin complex and cytoskeletal network, and transcriptional deregulation of genes involved in cell cycle and other pathways.
However, gain and loss are not the only mechanisms involved in the phenotypic heterogeneity of ANKRD1. Indeed, a recent publication by Cinquetti et al. (3) reports the identification of increased CARP expression or protein stability in 3 cases with total anomalous pulmonary venous return, a rare congenital heart defect characterized by failure of the pulmonary veins to connect to the left atrium during development. In this case, CARP overexpression or its increased activity are believed to repress normal cardiac gene expression, leading to abnormal heart development.
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Impact of ANKRD1 mutations discovery in clinical care
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The discovery of ANKRD1 mutations in cardiomyopathies has several implications. First, it contributes to fill the gap of the large number of patients in whom the cause of cardiomyopathy is still unknown, 40% of cases in HCM and probably 70% in DCM (11). Second, it expands our knowledge of the mechanisms leading to hypertrophy and heart failure to include abnormal stretch-based signaling in response to force: this appears to be another "common pathway" for HCM and DCM that could be targeted by novel therapeutic strategies. Finally, it raises the question of clinical genetic testing of ANKRD1 in HCM and DCM patients. Although the low prevalence of mutations may currently limit routine screening for the ANKRD1 gene, we may expect that the implementation of resequencing technology will allow a systematic screening for rare cardiomyopathy genes in these patients in the near future.
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Footnotes
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Supported by the National Institutes of Health (HL69071-01, MO1 RR00051-1575), American Heart Association 0150453N, and Muscular Dystrophy Association PN0007-056.
* 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 American College of Cardiology. 
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References
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1. Moulik M, Vatta M, Witt SH, et al. ANKRD1, the gene encoding cardiac ankyrin repeat protein, is a novel dilated cardiomyopathy gene J Am Coll Cardiol 2009;54:325-333.[Abstract/Free Full Text]2. Arimura T, Bos JM, Sato A, et al. Cardiac ankyrin repeat protein gene (ANKRD1) mutations in hypertrophic cardiomyopathy J Am Coll Cardiol 2009;54:334-342.[Abstract/Free Full Text] 3. Cinquetti R, Badi I, Campione M, et al. Transcriptional deregulation and a missense mutation define ANKRD1 as a candidate gene for total anomalous pulmonary venous return Hum Mutat 2008;29:468-474.[CrossRef][Web of Science][Medline] 4. Miller MK, Bang ML, Witt CC, et al. The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules J Mol Biol 2003;333:951-964.[CrossRef][Web of Science][Medline] 5. Zolk O, Frohme M, Maurer A, et al. Cardiac ankyrin repeat protein, a negative regulator of cardiac gene expression, is augmented in human heart failure Biochem Biophys Res Commun 2002;293:1377-1382.[CrossRef][Web of Science][Medline] 6. Itoh-Satoh M, Hayashi T, Nishi H, et al. Titin mutations as the molecular basis of dilated cardiomyopathy Biochem Biophys Res Commun 2002;291:385-391.[CrossRef][Web of Science][Medline] 7. Gerull B, Gramlich M, Atherton J, et al. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy Nature Genet 2002;30:201-204.[CrossRef][Web of Science][Medline] 8. Matsumoto Y, Hayashi T, Inagaki N, et al. Functional analysis of titin/connectin N2-B mutations found in cardiomyopathy J Muscle Res Cell Motil 2005;26:367-374.[CrossRef][Web of Science][Medline] 9. McKusick VA. Online Mendelian inheritance in man, OMIMMcKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD) 2000Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed June 8, 2009. 10. Haines J, Pericak-Vance M. Genetic Analysis of Complex Diseases2nd edition. Hoboken, NJ: Wiley & Sons; 2006. 11. Hershberger RE, Lindenfeld J, Mestroni L, Seidman CE, Taylor MR, Towbin JA. Genetic evaluation of cardiomyopathy—a Heart Failure Society of America Practice Guideline J Card Fail 2009;15:83-97.[CrossRef][Web of Science][Medline] 12. Mizra M, Marston S, Willot R, et al. Dilated cardiomyopathy mutations in 3 thin filament regulatory proteins result in a common functional phenotype J Biol Chem 2005;280:28498-28506.[Abstract/Free Full Text] 13. Kaski JP, Syrris P, Burch M, et al. Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes Heart 2008;94:1478-1484.[Abstract/Free Full Text] 14. Debold EP, Schmitt JP, Patlak JB, et al. Hypertrophic and dilated cardiomyopathy mutations differentially affect the molecular force generation of mouse alpha-cardiac myosin in the laser trap assay Am J Physiol Heart Circ Physiol 2007;293:H284-H291.[Abstract/Free Full Text] 15. Rajan S, Ahmed RP, Jagatheesan G, et al. Dilated cardiomyopathy mutant tropomyosin mice developcardiac dysfunction with significantly decreased fractional shortening and myofilament calcium sensitivity Circ Res 2007;101:205-214.[Abstract/Free Full Text] 16. Morimoto S. Sarcomeric proteins and inherited cardiomyopathies Cardiovasc Res 2008;77:659-666.[Abstract/Free Full Text]
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