Author + information
- Luisa Mestroni, MD⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Luisa Mestroni, Molecular Genetics, CUCVI, 12700 East 19th Avenue, Mail Stop F442, Aurora, Colorado 80045-6511
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).
ANKRD1in normal heart and disease
CARP is a 36 kD protein encoded by the cardiac ankyrin repeat domain 1 gene ANKRD1, which maps on chromosome 10. ANKRD1is 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).
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 ANKRD1mutations can cause both DCM and HCM.
Arimura et al. (2) report the results of the ANKRD1mutation screening in a large HCM population collected in Japan and in the U.S. In 384 index patients, they found 3 missense mutations (ANKRD1Pro52Ala, 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 (TTNArg8500 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 (ANKRD1Pro105Ser, 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?
Phenotypic heterogeneity in cardiomyopathies
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 ANKRD1mutations 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 ANKRD1mutations 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.
Impact of ANKRD1mutations discovery in clinical care
The discovery of ANKRD1mutations 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 ANKRD1in HCM and DCM patients. Although the low prevalence of mutations may currently limit routine screening for the ANKRD1gene, 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.
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 Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
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