title: 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.
  
  
  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.
authors.affiliation: Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA. olson.timothy@mayo.edu
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Olson
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Karst
authors.forename: Frank G
authors.initials: FG
authors.lastname: Whitby
authors.forename: David J
authors.initials: DJ
authors.lastname: Driscoll
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D019943:Amino Acid Substitution; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000175:diagnosis / Q000235:genetics*; D003241:Consanguinity; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D004452:Echocardiography; D004562:Electrocardiography; D005260:Female; D005808:Genes, Recessive; D006580:Genetic Carrier Screening; D008040:Genetic Linkage; D005838:Genotype; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D018994:Myosin Light Chains / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational
chemical_list: D018994:Myosin Light Chains