Molecular and phenotypic effects of heterozygous, homozygous, and compound heterozygote myosin heavy-chain mutations

Abstract

. Molecular and phenotypic effects of heterozygous, homozygous, and compound heterozygote myosin heavy-chain mutations. Am J Physiol Heart Circ Physiol 288: H1097-H1102, 2005. First published November 4, 2004 doi:10.1152/ajpheart.00650.2004.-Autosomal dominant familial hypertrophic cardiomyopathy (FHC) has variable penetrance and phenotype. Heterozygous mutations in MYH7 encoding ␤-myosin heavy chain are the most common causes of FHC, and we proposed that "enhanced" mutant actin-myosin function is the causative molecular abnormality. We have studied individuals from families in which members have two, one, or no mutant MYH7 alleles to examine for dose effects. In one family, a member homozygous for Lys207Gln had cardiomyopathy complicated by left ventricular dilatation, systolic impairment, atrial fibrillation, and defibrillator interventions. Only one of five heterozygous relatives had FHC. Leu908Val and Asp906Gly mutations were detected in a second family in which penetrance for Leu908Val heterozygotes was 46% (21/46) and 25% (3/12) for Asp906Gly. Despite the low penetrance, hypertrophy was severe in several heterozygotes. Two individuals with both mutations developed severe FHC. The velocities of actin translocation (V actin) by mutant and wild-type (WT) myosins were compared in the in vitro motility assay. Compared with WT/WT, V actin was 34% faster for WT/D906G and 21% for WT/L908V. Surprisingly V actin for Leu908Val/Asp906Gly and Lys207Gln/Lys207Gln mutants were similar to WT. The apparent enhancement of mechanical performance with mutant/WT myosin was not observed for mutant/mutant myosin. This suggests that V actin may be a poor predictor of disease penetrance or severity and that power production may be more appropriate, or that the limited availability of double mutant patients prohibits any definitive conclusions. Finally, severe FHC in heterozygous individuals can occur despite very low penetrance, suggesting these mutations alone are insufficient to cause FHC and that uncharacterized modifying mechanisms exert powerful influences.

Disease-Modifying Mutations in Familial Hypertrophic Cardiomyopathy

“…A few examples have been published recently, among them the k207q myh7 mutation, in which heterozygous individuals develop a hypertrophic phenotype but those with the homozygous variant (only 1 individual) develop a DCM-like phenotype. 9 Thus, the tni-203/mhc-403 mouse model supports the clinical observation that Ϸ5% of all individuals affected by FHC carry compound-and/or double-heterozygous mutations and exhibit a more severe phenotype.…”

Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

“…11,[39][40][41] Previously, isolated cases of digenic inheritance underlying diseases such as HCM have been identified by targeted Sanger sequencing of candidate genes, [6][7][8]42 but clearly, WES approaches now allow a comprehensive and systematic approach to questions of genetic modifiers and digenic inheritance. We therefore hypothesized that all family members affected by DCM would segregate an identical mutation, but that the severely affected persons could have an additional variant in the same or a second gene.…”

“…Recently, two or more sequence alterations present either in the same or in different genes were demonstrated to occur in 3-5% of cases of familial HCM, associated with a greater clinical severity of HCM. [6][7][8] Similarly, compound and digenic heterozygosity were identified in patients with arrhythmogenic right ventricular cardiomyopathy, whereby several desmosome and celljunction genes were found to carry more than one mutation likely associated with low penetrance. 9 It is to be expected that similar modifiers exist for DCM; even though a single case of a 14-year-old boy with manifestations of DCM and mutations in both MYH7 and TNNT2 has been published, 10 little is known about the genes and the molecular mechanisms involved in modifying the phenotype of familial DCM.…”

Targeted Next-Generation Sequencing for the Molecular Genetic Diagnostics of Cardiomyopathies

“…40,41 Recent studies identified numerous patients with cardiomyopathy who have more than 1 disease-causing mutation. [42][43][44] These mutations can occur in either the same gene (compound heterozygotes) or in different genes (double heterozygotes) in up to 5% of genetic cardiomyopathies. 45 As a consequence of these complex genotypes, the individual risk to develop end-stage disease or sudden cardiac death can strongly increase.…”