Hypertrophic Cardiomyopathy: How do Mutations Lead to Disease?

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common monogenic genetic cardiac disease, with an estimated prevalence of 1:500 in the general population. Clinically, HCM is characterized by hypertrophy of the left ventricle (LV) walls, especially the septum, usually asymmetric, in the absence of any cardiac or systemic disease that leads to a secondary hypertrophy. The clinical course of the disease has a large inter- and intrafamilial heterogeneity, ranging from mild symptoms of heart failure late in life to the onset of sudden cardiac death at a young age and is caused by a mutation in one of the genes that encode a protein from the sarcomere, Z-disc or intracellular calcium modulators. Although many genes and mutations are already known to cause HCM, the molecular pathways that lead to the phenotype are still unclear. This review focus on the molecular mechanisms of HCM, the pathways from mutation to clinical phenotype and how the disease's genotype correlates with phenotype.

Finding the candidate sequence variants for diagnosis of hypertrophic cardiomyopathy in East Slovak patients

“…Heterozygous missense single nucleotide changes were the most common types of detected sequence variants. Our findings are in consistency with the results of other authors . Among 43 identified sequence variants, four variants were identified in homozygosity (three sequence variants in exon 12 of NEBL gene and one in exon 9 of TNNT gene).…”

Animal Models of Congenital Cardiomyopathies Associated With Mutations in Z-Line Proteins

“…The clinical manifestations of HCM range from asymptomatic left ventricular hypertrophy to progressive heart failure, cardiac arrhythmias, and sudden cardiac death. Various molecular mechanisms have been proposed to underlie HCM, including altered calcium handling and sensitivity of the myofilament, alterations in the actomyosin interaction leading to abnormal myofibrillar force generation, and increased energy demand due to inefficient ATP utilization (“the energy depletion hypothesis”) (reviewed in Marsiglia and Pereira, ).…”

Myocardial collagen deposition and inflammatory cell infiltration in cats with pre-clinical hypertrophic cardiomyopathy

“…In human beings and cats, HCM is caused by mutations in genes that encode for the myofilament sarcomeric proteins, Z-disc proteins, calcium-handling proteins and other proteins related to the sarcomere (Ferrantini et al, 2009;Lehrer and Geeves, 2014). To date, 20 genes with over 400 missense mutations have been identified in human beings; there is strong evidence for pathogenicity for some of these mutations but less evidence for others (Ferrantini et al, 2009;Tian et al, 2013;Marsiglia and Pereira, 2014).…”