Myosin Light Chain Mutation Causes Autosomal Recessive Cardiomyopathy With Mid-Cavitary Hypertrophy and Restrictive Physiology

Abstract

Background-Autosomal dominant hypertrophic cardiomyopathy (HCM) is caused by inherited defects of sarcomeric proteins. We tested the hypothesis that homozygosity for a sarcomeric protein defect can cause recessive HCM. Methods and Results-We studied a family with early-onset cardiomyopathy in 3 siblings, characterized by mid-cavitary hypertrophy and restrictive physiology. Genotyping of DNA markers spanning 8 genes for autosomal dominant HCM revealed inheritance of an identical paternal and maternal haplotype at the essential light chain of myosin locus by the affected children. Sequencing showed that these individuals were homozygous for a Glu143Lys substitution of a highly conserved amino acid that was absent in 150 controls. Family members with one Glu143Lys allele had normal echocardiograms and ECGs, even in late adulthood, whereas those with two mutant alleles developed severe cardiomyopathy in childhood. These findings, coupled with previous studies of myosin light chain structure and function in the heart, suggest a loss-of-function disease mechanism. Conclusions-Distinct mutations affecting the same sarcomeric protein can cause either dominant or recessive cardiomyopathy. Electrostatic charge reversal of a highly conserved amino acid may be benign in the heterozygous state as the result of compensatory mechanisms that preserve cardiac structure and function. By contrast, homozygous carriers of a sarcomeric protein defect may have a malignant course. Recognizing recessive inheritance in children with cardiomyopathy is essential for appropriate family counseling.

Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy

“…Research interests in the ELC of myosin as a potential regulator of cardiac muscle contraction have been high since the discovery of several FHC-associated mutations in the MYL3 gene that encodes for the ventricular myosin ELC (13,22,29,37,41,43,45). Compared with the ␤-MHC, genetic mutations in the ELC are rare but they are also associated with malignant outcomes (3,13,17,29,42).…”

“…Notably, FHC has been considered the leading cause of SCD in the young, especially in athletes (33,47). Compared with the ␤-MHC or cardiac myosin binding protein-C (cMyBP-C), FHC-linked mutations in the ventricular ELC are rare, but they are also associated with SCD (13,22,29,37,41,43,45). In this report, we focus on the A57G (alanine to glycine) mutation implicated in malignant FHC outcomes (29).…”

Hypertrophic Cardiomyopathy: Low Frequency of Mutations in the β-Myosin Heavy Chain (MYH7) and Cardiac Troponin T (TNNT2) Genes among Spanish Patients

“…Overall, MYH7 would be mutated in 10 -30% of families, whereas the genes encoding cardiac troponin T (TNNT2) on chromosome 1q3, ␣-tropomyosin (TPMA) on chromosome 15q2, and myosin-binding protein C (MYBPC) on chromosome 11p11.2 are responsible for another 15-30% (12-16 ). Recently, mutations in other genes, such those that encode for the myosin essential and regulatory light chains, cardiac troponin I (TNNI3), and titin, have been identified in some HC patients (17)(18)(19).…”

Impact of Genetic Insights Into Mendelian Disease on Cardiovascular Clinical Practice

“…Numerous mutations have been identified in Ϸ20 different genes to date (Table 1). [2][3][4][5][6][7][8][9][10][11] Despite the high prevalence of this disorder, the annual mortality from HCM remains relatively low, and it still remains a challenging task for practicing clinicians to identify which individuals are at significant risk for SCD. 12 Although the American College of Cardiology/ American Heart Association guideline classifies implantable cardioverter-defibrillator (ICD) therapy as a class I indication in patients with sustained ventricular tachycardia (VT) or ventricular fibrillation, the real challenge is to identify these individuals before the onset of potentially catastrophic events.…”