RNA Splicing Defects in Hypertrophic Cardiomyopathy: Implications for Diagnosis and Therapy.

Marta Ribeiro,Maria Carmo-Fonseca,Teresa Carvalho,Sandra Martins,Marta Furtado

doi:10.3390/ijms21041329

Abstract

Hypertrophic cardiomyopathy (HCM), the most common inherited heart disease, is predominantly caused by mutations in genes that encode sarcomere-associated proteins. Effective gene-based diagnosis is critical for the accurate clinical management of patients and their family members. However, the introduction of high-throughput DNA sequencing approaches for clinical diagnostics has vastly expanded the number of variants of uncertain significance, leading to many inconclusive results that limit the clinical utility of genetic testing. More recently, developments in RNA analysis have been improving diagnostic outcomes by identifying new variants that interfere with splicing. This review summarizes recent discoveries of RNA mis-splicing in HCM and provides an overview of research that aims to apply the concept of RNA therapeutics to HCM.

Highlights

Familial hypertrophic cardiomyopathy (HCM), the most common inherited heart disease, is predominantly caused by mutations in genes that encode proteins associated with the cardiac sarcomere
HCM mutations in the MYBPC3 gene resulted in the reduced expression of myosin-binding protein C and caused altered cardiac function [53]. These results suggest that MYBPC3 haplo-insufficiency is a pathologic mechanism for HCM
Chimeric molecules resulting from trans-splicing represented less than 1% of all MYBPC3 mRNAs in cardiomyocytes, indicating that the efficiency of this approach was too low to be considered as a therapeutic option [79]

Summary

Introduction

Familial hypertrophic cardiomyopathy (HCM), the most common inherited heart disease, is predominantly caused by mutations in genes that encode proteins associated with the cardiac sarcomere. Two-thirds of patients with HCM are asymptomatic or minimally symptomatic [3,4,5], and the most frequent symptoms include exertional dyspnea, chest pain, and arrhythmias [6,7] These symptoms can be relentlessly progressive with resultant heart failure, underscoring the importance of therapeutic strategies to slow, halt, or reverse disease progression [6,7]. A positive test supports an HCM diagnosis in individuals with a septal thickness below the cutoff point for clinical diagnosis [12,13] Another important contribution of genetic testing is that it allows for a distinction between HCM and so-called phenocopy conditions, i.e., apparently similar disorders with different causes. For the majority of HCM patients, a positive genetic test is unable to predict the clinical course of the disease or the risk of complications, including sudden cardiac death and heart failure. We discuss emerging strategies for HCM-targeted RNA therapeutics

RNA Splicing Mechanisms

Disease-Causing Splicing Mutations

HCM-Associated Splicing Mutations

RNA Therapeutics for HCM

Findings

Concluding Remarks