Expanded spectrum of gene causing both hypertrophic cardiomyopathy and dilated cardiomyopathy.

Cardiomyopathy can be classified into at least four main forms, hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), restrictive cardiomyopathy, and left ventricular noncompaction. HCM produces ventricular wall thickening, especially in the interventricular septum, with decrease in ventricular chamber volumes. DCM produces a prominent increase in chamber volumes without ventricular wall thickening. In HCM, systolic function is increased or at least preserved, whereas diastolic function is impaired in part because of the hypertrophy itself, interstitial fibrosis, and/or myocyte disarrays. Diastolic dysfunction is thought to be responsible for symptoms of heart failure and premature sudden cardiac death of HCM patients. In contrast, DCM is characterized by systolic dysfunction, which leads to congestive heart failure requiring cardiac transplantation. Restrictive cardiomyopathy is characterized by restrictive diastolic dysfunction (restrictive filling and reduced diastolic volume of either or both ventricles) with normal or near normal systolic function and wall thickness. Left ventricular noncompaction is characterized by deep trabeculation in the ventricular wall with systolic and diastolic dysfunction, arrhythmias, and thromboembolic events. More than 400 mutations that cause HCM, DCM, restrictive cardiomyopathy, and left ventricular noncompaction have been found in the genes for proteins constituting the sarcomere of cardiac muscle in human, including and -myosin heavy chains, -cardiac actin, cardiac troponin (cTn)T, cTnI, cTnC, -tropomyosin ( TM), cardiac myosinbinding protein-C, cardiac myosin essential light chain, cardiac myosin regulatory light chain, and cardiac titin/connectin. Most mutations cause cardiomyopathies in an autosomal dominant manner. Interestingly, the same sarcomeric gene was found to be simultaneously responsible for different forms of cardiomyopathy.1,2 For example, many mutations in cTnT, cTnC, -tropomyosin, -cardiac actin, -myosin heavy chain, and titin have been found in both HCM and primary DCM that is clearly distinguished from an end-stage dilated phase of HCM. This strongly suggests that the location of mutation, and thus its specific consequences on protein structure and function play an important role in the distinctive phenotypic variation between HCM and DCM. Many mutations in cTnI have also been found in both HCM and restrictive cardiomyopathy. Surprisingly, however, no mutations in cTnI were found to cause autosomal dominant DCM, with only one mutation, A2V, being reported to cause a rare case of DCM inherited in a “recessive” manner.3 In this issue of Circulation Research, Carballo et al4 identified the first mutations in TNNI3 (cTnI gene), K36Q and N185K, to cause autosomal dominant DCM by testing TNNI3 as a candidate gene in a panel of probands with DCM and expanded the spectrum of disease genes that lead to either HCM or DCM depending on the specific mutation. The K36Q mutation is in a postulated hinge region that mediates the movement of the N-terminal region in cTnI on phosphorylation of S22/23 by cAMP-dependent protein kinase.5 The N185K mutation is in an -helix of cTnI that binds to actin-tropomyosin. These mutations were each found in small single families with severe and early onset DCM. In the family with the K36Q mutation, the proband and his younger son carrying mutation were diagnosed with severe DCM at age 15 and 6, respectively, with a rapid deterioration requiring early cardiac transplantation. The older son of the proband carrying mutation was diagnosed with mild DCM at the age of 7 on screening. In the family with the N185K mutation, the proband was diagnosed with severe DCM at the age of 24, and 13 months later, he underwent cardiac transplantation. His father was diagnosed with DCM at the age of 50. After 4 years without symptoms, the father required cardiac resynchronization therapy but died from complications. In each family, the mutation identified cosegregated with disease. Unfortunately, the genetic linkage of DCM to these mutations could not exclusively be demonstrated because of the small family sizes, so that they further investigated the functional impacts of these mutations in cTnI in an elegant manner using synthetic thin filaments to obtain additional strong evidence of pathogenicity. They reconstituted thin filaments using physiological stoichiometric amounts of rabbit skeletal muscle actin, recombinant human TM, and recombinant human cardiac troponin, 7:1:1 respectively. Thin filaments reconstituted with cTnI with the putative DCM mutations conferred decreased maximum activity and Ca sensitivity on rabbit skeletal muscle myosin S1 ATPase activity compared to those reconstituted with wildtype cTnI. Furthermore, they showed that the Ca binding affinity of the regulatory site II of cTnC was significantly reduced in the thin filament containing mutant cTnIs by using a fluorescently labeled cTnC as a reporter. These results strongly suggest that both the K36Q and N185K mutations in TNNI3 cause DCM via a similar pathogenic mechanism to the DCM mutations found in other The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. Department of Clinical Pharmacology, Kyushu University Graduate School of Medicine, Fukuoka, Japan. Correspondence to Sachio Morimoto, Department of Clinical Pharmacology, Kyushu University Graduate School of Medicine, Fukuoka 812-8582, Japan. E-mail [email protected] (Circ Res. 2009;105:313-315.) © 2009 American Heart Association, Inc.