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Published on: July 29, 2016
Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive
Timothy M Olson1, Margaret L Karst, Frank G Whitby
1Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA. olson.timothy@mayo.edu
Insights
Homozygosity for a sarcomeric protein defect can cause recessive hypertrophic cardiomyopathy (HCM). Recessive inheritance of this condition in children is crucial for accurate family genetic counseling.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Basis of Cardiomyopathy
Background:
- Autosomal dominant hypertrophic cardiomyopathy (HCM) is linked to sarcomeric protein defects.
- This study investigates if homozygous sarcomeric protein defects can cause recessive HCM.
Purpose of the Study:
- To test the hypothesis that homozygosity for a sarcomeric protein defect can cause recessive HCM.
- To identify the genetic basis of early-onset cardiomyopathy in a family with affected siblings.
Main Methods:
- Studied a family with three siblings presenting with early-onset cardiomyopathy.
- Performed genotyping for autosomal dominant HCM genes and sequenced the essential light chain of myosin locus.
- Analyzed DNA markers and identified homozygous mutations in affected individuals and heterozygous carriers.
Main Results:
- Affected siblings were homozygous for the Glu143Lys substitution in the essential light chain of myosin.
- Family members with one Glu143Lys allele showed normal cardiac function, while homozygous carriers developed severe childhood cardiomyopathy.
- The mutation was absent in 150 healthy controls, suggesting a loss-of-function mechanism.
Conclusions:
- Different mutations in the same sarcomeric protein can lead to dominant or recessive cardiomyopathy.
- Homozygous carriers of sarcomeric protein defects may experience severe, malignant cardiac courses.
- Identifying recessive inheritance patterns is vital for genetic counseling in pediatric cardiomyopathy cases.
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.
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