Mutation in the alpha-cardiac actin gene associated with apical hypertrophic cardiomyopathy, left ventricular non-compaction, and septal defects

Monserrat, Lorenzo; Hermida-Prieto, Manuel; Fernández, Xusto; Rodríguez, Isabel; Dumont, C; Cazón, Laura; Cuesta, M. González; González‐Juanatey, Carlos; Peteiro, Jesús; Álvarez, Nemesio; Penas-Lado, Manuel; Castro‐Beiras, Alfonso

doi:10.1093/eurheartj/ehm239

Cited by 225 publications

(153 citation statements)

References 34 publications

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“…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.…”

Section: Hypertrophic Cardiomyopathy (Hcm)mentioning

confidence: 99%

“…The ACTC E99K mutation is the subject of an extensive ongoing clinical study with 76 mutation carriers in 10 families currently identified (13). This mutation is associated with a unique form of hypertrophy where the apex of the heart is thickened, with a phenotype overlapping both HCM and left ventricular hypertrabeculation/noncompaction.…”

Section: Hypertrophic Cardiomyopathy (Hcm)mentioning

confidence: 99%

“…Although mutations in ACTC are not a common cause of HCM, the clinical consequences of the ACTC E99K mutation have been studied in a large population (13). Hypertrophy was reported from 62 of 76 mutation carriers.…”

Section: Actc E99k Mouse Model Of Hcm-we Developed Thementioning

confidence: 99%

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

Song

Dyer

Stuckey

et al. 2011

Journal of Biological Chemistry

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We generated a transgenic mouse model expressing the apical hypertrophic cardiomyopathy-causing mutation ACTC E99K at 50% of total heart actin and compared it with actin from patients carrying the same mutation. The actin mutation caused a higher Ca 2؉ sensitivity in reconstituted thin filaments measured by in vitro motility assay (2.3-fold for mice and 1.3-fold for humans) and in skinned papillary muscle. The mutation also abolished the change in Ca 2؉ sensitivity normally linked to troponin I phosphorylation. MyBP-C and troponin I phosphorylation levels were the same as controls in transgenic mice and human carrier heart samples. ACTC E99K mice exhibited a high death rate between 28 and 45 days (48% females and 22% males). At 21 weeks, the hearts of the male survivors had enlarged atria, increased interstitial fibrosis, and sarcomere disarray. MRI showed hypertrophy, predominantly at the apex of the heart. End-diastolic volume and end-diastolic pressure were increased, and relaxation rates were reduced compared with nontransgenic littermates. End-systolic pressures and volumes were unaltered. ECG abnormalities were present, and the contractile response to ␤-adrenergic stimulation was much reduced. Older mice (29-week-old females and 38-week-old males) developed dilated cardiomyopathy with increased end-systolic volume and continuing increased end-diastolic pressure and slower contraction and relaxation rates. ECG showed atrial flutter and frequent atrial ectopic beats at rest in some ACTC E99K mice. We propose that the ACTC E99K mutation causes higher myofibrillar Ca 2؉ sensitivity that is responsible for the sudden cardiac death, apical hypertrophy, and subsequent development of heart failure in humans and mice.

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Section: Hypertrophic Cardiomyopathy (Hcm)mentioning

confidence: 99%

Section: Hypertrophic Cardiomyopathy (Hcm)mentioning

confidence: 99%

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

Song

Dyer

Stuckey

et al. 2011

Journal of Biological Chemistry

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“…Furthermore, the p.(Ala21Val) mutation strongly cosegregates with the disease, providing additional support for its pathogenicity. ACTC1 gene mutations have been phenotypically related with diverse cardiac anomalies, including dilated cardiomyopathy,17 hypertrophic cardiomyopathy,18, 19, 20 myocardial noncompaction,8, 21 and congenital heart defects, in particular atrial septal defect 22…”

Section: Discussionmentioning

confidence: 99%

“…Other genes whose mutations have been implicated in both HCM and LVNC are TPM1 and MYBPC3 , encoding for tropomyosin 1 and cardiac myosin binding protein‐C, respectively 7, 8, 9, 10, 11, 12, 13…”

mentioning

confidence: 99%

Novel α‐Actin Gene Mutation p.(Ala21Val) Causing Familial Hypertrophic Cardiomyopathy, Myocardial Noncompaction, and Transmural Crypts. Clinical‐Pathologic Correlation

Frustaci

Luca

Guida

et al. 2018

JAHA

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BackgroundMutations of α‐actin gene (ACTC1) have been phenotypically related to various cardiac anomalies, including hypertrophic cardiomyopathy and dilated cardiomyopathy and left ventricular (LV) myocardial noncompaction. A novel ACTC mutation is reported as cosegregating for familial hypertrophic cardiomyopathy and LV myocardial noncompaction with transmural crypts.Methods and ResultsIn an Italian family of 7 subjects, 4 aged 10 (II‐1), 14 (II‐2), 43 (I‐4) and 46 years (I‐5), presenting abnormal ECG changes, dyspnea and palpitation (II‐2, I‐4, and I‐5), and recurrent cerebral ischemic attack (I‐5), underwent 2‐dimensional echo, cardiac magnetic resonance, Holter monitoring, and next‐generation sequencing gene analysis. Patients II‐2 and I‐5 with ventricular tachycardia underwent a cardiac invasive study, including coronary with LV angiography and endomyocardial biopsy. In all the affected members, ECG showed right bundle branch block and left anterior hemiblock with age‐related prolongation of QRS duration. Two‐dimensional echo and cardiac magnetic resonance documented LV myocardial noncompaction in all and in I‐4, I‐5, and II‐2 a progressive LV hypertrophy up to 22‐mm maximal wall thickness. Coronary arteries were normal. LV angiography showed transmural crypts progressing to spongeous myocardial transformation with LV dilatation and dysfunction in the oldest subject. At histology and electron microscopy detachment of myocardiocytes were associated with cell and myofibrillar disarray and degradation of intercalated discs causing disanchorage of myofilaments to cell membrane. Next‐generation sequencing showed in affected members an unreported p.(Ala21Val) mutation of ACTC.ConclusionsNovel p.(Ala21Val) mutation of ACTC1 causes myofibrillar and intercalated disc alteration leading to familial hypertrophic cardiomyopathy and LV myocardial noncompaction with transmural crypts.

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Left ventricular noncompaction in patients with β‐thalassemia: Uncovering a previously unrecognized abnormality

et al. 2012

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Left ventricular noncompaction (LVNC) is a rare cardiomyopathy with potentially serious outcomes. It results in multiple and excessive trabeculations, deep intertrabecular recesses, and a thickened ventricular myocardium with two distinct layers, compacted and noncompacted. The condition is most commonly congenital; however, acquired forms have also been described. A recent report of LVNC detected in a bthalassemia twin suggested an association with cardiac siderosis. In a cross-sectional study of 135 transfusion-dependent patients with b-thalassemia (130 major and 5 intermedia, mean age 29.6 ± 7.7 years, 49.6% males) presenting for cardiac iron assessment by magnetic resonance imaging (MRI), we evaluated the prevalence and risk factors for LVNC. None of the patients had neuromuscular or congenital heart disease. Eighteen patients (13.3%; 95% confidence interval [CI] 5 8.6-20.1) fulfilled the preassigned strict criteria for LVNC on cardiac MRI. There were no statistically significant differences between patients with and without LVNC with respect to demographics; hemoglobin levels; splenectomy status; systemic, hepatic, and cardiac iron overload indices; hepatic disease and infection studies; or iron chelator type. Patients with LVNC were more likely to have heart failure (adjusted odds ratio 5 1.77; 95% CI 5 0.29-10.89); although with high uncertainty. Patients with b-thalassemia have a higher prevalence of LVNC than normal individuals. As this finding could not be explained by conventional risk factors in this patient population, further investigation of the underlying mechanisms of LVNC is warranted. This remains crucial for an entity with adverse cardiac outcomes, especially in patients with b-thalassemia where cardiac disease remains a primary cause of mortality. Am. J. Hematol. 87:1079Hematol. 87: -1083Hematol. 87: , 2012

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Mutation in the alpha-cardiac actin gene associated with apical hypertrophic cardiomyopathy, left ventricular non-compaction, and septal defects

Abstract: LVNC and HCM may appear as overlapping entities. The ACTC E101K mutation should be considered in the genetic diagnosis of LVNC, apical HCM, and septal defects.

Cited by 225 publications

References 34 publications

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

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

Novel α‐Actin Gene Mutation p.(Ala21Val) Causing Familial Hypertrophic Cardiomyopathy, Myocardial Noncompaction, and Transmural Crypts. Clinical‐Pathologic Correlation

Left ventricular noncompaction in patients with β‐thalassemia: Uncovering a previously unrecognized abnormality

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