A novel Myosin essential light chain mutation causes hypertrophic cardiomyopathy with late onset and low expressivity

Abstract

Hypertrophic cardiomyopathy (HCM) is caused by mutations in genes encoding sarcomere proteins. Mutations in MYL3, encoding the essential light chain of myosin, are rare and have been associated with sudden death. Both recessive and dominant patterns of inheritance have been suggested. We studied a large family with a 38-year-old asymptomatic HCM-affected male referred because of a murmur. The patient had HCM with left ventricular hypertrophy (max WT 21 mm), a resting left ventricular outflow gradient of 36 mm Hg, and left atrial dilation (54 mm). Genotyping revealed heterozygosity for a novel missense mutation, p.V79I, in MYL3. The mutation was not found in 300 controls, and the patient had no mutations in 10 sarcomere genes. Cascade screening revealed a further nine heterozygote mutation carriers, three of whom had ECG and/or echocardiographic abnormalities but did not fulfil diagnostic criteria for HCM. The penetrance, if we consider this borderline HCM the phenotype of the p.V79I mutation, was 40%, but the mean age of the nonpenetrant mutation carriers is 15, while the mean age of the penetrant mutation carriers is 47. The mutation affects a conserved valine replacing it with a larger isoleucine residue in the region of contact between the light chain and the myosin lever arm. In conclusion, MYL3 mutations can present with low expressivity and late onset.

Figure 1

The structure of the myosin S1 fragment (red) with the essential (ELC) (yellow) and regulatory (RLC) (blue) light chains marked. The structure is based on the X-ray crystallographic data available in the form of the 2MYS pdb file [43].

Figure 2

The genomic structure of MYL3 with the localization of known disease causing mutations indicated.

Figure 3

The pedigree of the examined family, the proband is marked by arrow. He is the only clinically affected (black symbol), + indicates family members who are heterozygous for the p.V79I mutation, − indicates family members who were genetically assessed and found to be nonmutation carriers. The three family members with borderline HCM are marked by a black quadrant. SB: still birth. SD marks a 19-year-old girl who suddenly died. No further information was available as to the cause of death.

Figure 4

A homology analysis of the known MYL3 mutations, the valine in residue 79 is highly conserved.

Figure 5

The location of the p.V79I mutation (arrow) in the three-dimensional structure of the regulatory domain of myosin (red) with the essential (ELC) (blue) and regulatory (RLC) (yellow) light chain. The other known mutations in ELC are also marked. It is seen that the p.V79I mutation; as well as the pR81H and p.M149V mutation, is located close to the IQ1 motif of the myosin helix. The IQ1 motif is marked by a white arrow. The figure is based on X-ray crystallographic structure of the myosin myosin regulatory domain of the scallop as given in the 1WDC pdb file [32].