Progress in the Molecular Genetics of Hypertrophic Cardiomyopathy: A Mini-Review

Abstract

Background: Hypertrophic cardiomyopathy (HCM), which is characterized by unexplained and asymmetric left ventricular hypertrophy in the absence of other cardiac or systemic diseases, is an inherited cardiovascular disease and presents rising penetrance with aging. Objective: The purpose of this review is to offer an outline of recent progress in the molecular genetics of HCM and to discuss characteristics of elderly HCM patients. Methods: Studies were analyzed which included disease genes related to HCM, relationships between genotype and phenotype, potential pathogenesis of HCM, and the features of elderly patients with HCM. Results: HCM is caused by mutations in genes encoding myofilament proteins of the sarcomere, Z-disc proteins, Ca²⁺-handling proteins, and other proteins related to the sarcomere. Phenotypic manifestations of HCM are not just determined by these genes; modifying genes and epigenetic factors also contribute to the complexity of the HCM phenotype. The potential pathogenesis of HCM involves dominant negative function, an imbalance of myocardial energetic metabolism, and haploinsufficiency. Late-onset HCM presents its own features in the distribution of causal genes. Mutations in MYBPC3 may be the most common cause of delayed expression of HCM, and the sarcomere gene screen is most likely to be negative in elderly HCM patients. Conclusions: Despite progress in the identification of genetic causes and pathogenesis of HCM, there are still some questions that need to be better understood. It remains a great challenge to identify the cause of 50% of HCM cases in patients without an identified mutation. The application of a new genetic study technology may completely uncover the genetic background of these cases. In addition, the influences of causal mutations on the function and signaling of cardiocytes are expected to be elucidated further.

The genetic basis of hypertrophic cardiomyopathy in cats and humans

“…They include mutations in genes that encode for proteins in the Z-disc (e.g., muscle LIM protein, telethonin, vinculin, LIM domain binding 3, α-actinin 2, myozenin 2, cardiac ankyrin repeat protein, nexilin), and calcium handling protein genes (e.g., phospholamban, calsequestrin 2, calreticulin 3, junctophilin 2). 8,12 Many of these have been identified in only one or a few families and thus a solid causal relationship has not been established in all.…”

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).…”

A Double Heterozygous Mutation of <b><i>TNNI3</i></b> Causes Hypertrophic Cardiomyopathy in a Han Chinese Family

“…Previous studies indicated that the pathogenesis of HCM involves a dominant negative function, an imbalance of myocardial energetic metabolism and haploinsufficiency [13]. In this family, HCM caused by the 2 mutations may be explained by haploinsufficiency for the decreased expression of abnormal protein; the protein expression analysis proved that the mutants could not produce enough to bring about a WT condition.…”