Genetic, clinical, molecular, and pathogenic aspects of the South Asian-specific polymorphic MYBPC3Δ25bp variant

Abstract

Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease characterized by ventricular enlargement, diastolic dysfunction, and increased risk for sudden cardiac death. Sarcomeric genetic defects are the predominant known cause of HCM. In particular, mutations in the myosin-binding protein C gene (MYBPC3) are associated with ~ 40% of all HCM cases in which a genetic basis has been established. A decade ago, our group reported a 25-base pair deletion in intron 32 of MYBPC3 (MYBPC3^Δ25bp) that is uniquely prevalent in South Asians and is associated with autosomal dominant cardiomyopathy. Although our studies suggest that this deletion results in left ventricular dysfunction, cardiomyopathies, and heart failure, the precise mechanism by which this variant predisposes to heart disease remains unclear. Increasingly appreciated, however, is the contribution of secondary risk factors, additional mutations, and lifestyle choices in augmenting or modifying the HCM phenotype in MYBPC3^Δ25bp carriers. Therefore, the goal of this review article is to summarize the current research dedicated to understanding the molecular pathophysiology of HCM in South Asians with the MYBPC3^Δ25bp variant. An emphasis is to review the latest techniques currently applied to explore the MYBPC3^Δ25bp pathogenesis and to provide a foundation for developing new diagnostic strategies and advances in therapeutics.

Keywords: Heart failure; Hypertrophic cardiomyopathy; MYBPC3; South Asian.

Fig. 1

Genotype of MYBPC3^Δ25bp in intron 32 of the MYBPC3 gene. (a) Two options of 25-bp deletion are indicated with the same outcome. (b) The location of the splice branch point and polypyrimidine track at the junction of intron 32/exon 33 splicing (modified from Sadayappan et al. 2020)

Fig. 2

Prevalence of MYBPC3^Δ25bp worldwide. The frequency of MYBPC3^Δ25bp distribution in various countries is shown as a percentage. Details are provided in Table 1 with the total number of samples screened by the country concerning the existing literature

Fig. 3

cMyBP-C: structure, localization, and function illustrating the location of both MYBPC3^Δ25bp and MYBPC3^D389V variants. (a) MYBPC3 gene comprising 35 exons and 35 introns. (b) cMyBP-C codes for 1273 amino acids of cMyBP-C protein containing several domains. (c) cMyBP-C is located on 7–9 stripes of 43 nm spacing in each half of the A-band (cross-bridge bearing zone, C-region) of the sarcomere exclusively in cardiac myocytes. Both MYBPC3^Δ25bp and MYBPC3^D389V variants are indicated in the MYBPC3 gene and cMyBP-C protein. cMyBP-C is an important structural component of the sarcomere which plays a regulatory role in cardiac muscle function via interacting with actin, myosin, and titin. cMyBP-C, cardiac myosin-binding protein C; MYBPC3, cardiac myosin-binding protein C3 gene

Fig. 4

Possible mechanisms for MYBPC3^Δ25bp pathogenesis. Representation of various possible mechanisms of MYBPC3^Δ25bp in cardiomyocytes with the strong probability of another unidentified phenomenon causing left ventricular hypertrophy (LVH), left ventricular dysfunction (LVD), HCM, and HF. Eight related mechanisms range from abnormal gene transcription to defective translated protein

Fig. 5

MYBPC3^Δ25bp and MYBPC3^Δ25bp/D389V variants and associated pathogenesis. (a) Schematic illustration showing transcription of non-carrier MYBPC3 allele coding normal cMyBP-C protein. (b) Intron 32 carrying MYBPC3^Δ25bp mutation drives splicing defect causing exon 33 skipping and coding mutated C10 domain (cMyBP-C^ΔC10mut). (c) Similarly, an additional point mutation, i.e., D389V, along with MYBPC3^Δ25bp (together represented as MYBPC3^Δ25bp/D389V), is also presented. Such mutations drive abnormal MYBPC3 gene transcription and translation leading to diverse processes/pathways that have adverse effects on cardiomyocyte health that may result in cardiomyopathy phenotype