Gene Mutations in Apical Hypertrophic Cardiomyopathy

Abstract

Background-Nonobstructive hypertrophy localized to the cardiac apex is an uncommon morphological variant of hypertrophic cardiomyopathy (HCM) that often is further distinguished by distinct giant negative T waves and a benign clinical course. The genetic relationship between HCM with typical hypertrophic morphology versus isolated apical hypertrophy is incompletely understood. Methods and Results-Genetic cause was investigated in 15 probands with apical hypertrophy by DNA sequence analyses of 9 sarcomere protein genes and 3 other genes (GLA, PRKAG2, and LAMP2) implicated in idiopathic cardiac hypertrophy. Six sarcomere gene mutations were found in 7 samples; no samples contained mutations in GLA, PRKAG2, or LAMP2. Clinical evaluations demonstrated familial apical HCM in 4 probands, and in 3 probands disease-causing mutations were identified. Two families shared a cardiac actin Glu101Lys missense mutation; all members of both families with clinical manifestations of HCM (nϭ16) had apical hypertrophy. An essential light chain missense mutation Met149Val caused apical or midventricular segment HCM in another proband and 5 family members, but 6 other affected relatives had typical HCM morphologies. No other sarcomere gene mutations identified in the remaining probands caused apical HCM in other family members. Conclusions-Sarcomere protein gene mutations that cause apical hypertrophy rather than more common HCM morphologies reflect interactions among genetic etiology, background modifier genes, and/or hemodynamic factors. Only a limited number of sarcomere gene defects (eg, cardiac actin Glu101Lys) consistently produce apical HCM.

Molecular Mechanism of the E99K Mutation in Cardiac Actin (ACTC Gene) That Causes Apical Hypertrophy in Man and Mouse

“…This does not seem to be due to genetic background because apical hypertrophy co-segregates with the ACTC E99K mutation in families that have unrelated haplotypes (12). In our transgenic mice, hypertrophy was also confined to the apex of the heart, thus confirming that apical hypertrophy is a direct consequence of the ACTC E99K mutation.…”

“…More than 600 mutations have been discovered to be associated with HCM with all but a few in the genes coding for the contractile apparatus of the myofibril, predominantly myosin-binding protein C and ␤-myosin heavy chain (3)(4)(5)(6). Eleven mutations have been identified in the cardiac actin gene, ACTC (7)(8)(9)(10)(11), including the E99K mutation that has been intensively investigated as it has been shown to co-segregate with an unusual apical hypertrophic phenotype (12,13). HCM is defined clinically as the presence of unexplained ventricular hypertrophy; usually the thickening is most prominent in the interventricular septum, but other pathologies can also occur, such as apical and concentric hypertrophy or left ventricular noncompaction.…”

New mutation of mitochondrial DNAJC19 causing dilated and noncompaction cardiomyopathy, anemia, ataxia, and male genital anomalies

“…The combination of cardiomyopathy phenotypes (dilated and noncompacted) observed in our patients support the recent suggestions that there are shared molecular etiologies for different types of cardiomyopathies (18).…”

A Failure to Communicate

“…In patients, the E497D mutation results in apical hypertrophic cardiomyopathy, which is limited to the left ventricular apex (5). The effects of this mutation can be compounded by coronary artery disease, in that a relative of the proband with both coronary artery disease and the HCM mutation displayed massive concentric hypertrophy (5).…”

“…The effects of this mutation can be compounded by coronary artery disease, in that a relative of the proband with both coronary artery disease and the HCM mutation displayed massive concentric hypertrophy (5). Although the mutant E497D residue retains its negative charge, its reduced bulkiness results in a greater distance between residues 497 and 712, obviating a strong charge interaction (Fig.…”