Background: Protein aggregate myopathies are increasingly recognized conditions characterized by a surplus of endogenous proteins. The molecular and mutational background for many protein aggregate myopathies, has been clarified with the discovery of several underlying mutations. Familial idiopathic hyperCKaemia is a benign genetically heterogeneous condition, with autosomal dominant features in a high proportion of cases. Methods: In 10 patients from 3 Italian families with autosomal dominant benign vacuolar myopathy and hyperCKaemia we performed linkage analysis and exome sequencing as well as morphological and biochemical investigations. Results and Conclusions: We found, by exome and Sanger sequencing, that the condition is due to a D238G heterozygous missense mutation in the CASQ1 gene. Microsatellite analysis revealing a common haplotype in the 3 families indicated consanguinity and a founder effect. Immunocytochemistry, electron microscopy, biochemistry, and transfected cell line investigations showed a tendency of the mutated protein to form aggregates. The mutation, by altering CASQ1 polymerization, is likely to modify CASQ1’s interaction with the ryanodine receptor, compromising ryanodine receptor-mediated Ca2+ release from the sarcoplasmic reticulum. The mutation may also impair Ca2+ buffering capacity of CASQ1, and protein aggregates might have a toxic effect on muscle fibers. The likely outcome is sarcomere destabilization, altered mechanotransduction and contraction, fiber necrosis and increased plasma CK. HyperCKaemia in this condition is common and sometimes the sole overt manifestation. It is possible that CASQ1 mutations may go undiagnosed, if a muscle biopsy is not taken, and that the condition is more frequent than supposed.
A CASQ1 founder mutation in three Italian families with protein aggregate myopathy and hyperCKaemia
PESSIA, Mauro;
2015
Abstract
Background: Protein aggregate myopathies are increasingly recognized conditions characterized by a surplus of endogenous proteins. The molecular and mutational background for many protein aggregate myopathies, has been clarified with the discovery of several underlying mutations. Familial idiopathic hyperCKaemia is a benign genetically heterogeneous condition, with autosomal dominant features in a high proportion of cases. Methods: In 10 patients from 3 Italian families with autosomal dominant benign vacuolar myopathy and hyperCKaemia we performed linkage analysis and exome sequencing as well as morphological and biochemical investigations. Results and Conclusions: We found, by exome and Sanger sequencing, that the condition is due to a D238G heterozygous missense mutation in the CASQ1 gene. Microsatellite analysis revealing a common haplotype in the 3 families indicated consanguinity and a founder effect. Immunocytochemistry, electron microscopy, biochemistry, and transfected cell line investigations showed a tendency of the mutated protein to form aggregates. The mutation, by altering CASQ1 polymerization, is likely to modify CASQ1’s interaction with the ryanodine receptor, compromising ryanodine receptor-mediated Ca2+ release from the sarcoplasmic reticulum. The mutation may also impair Ca2+ buffering capacity of CASQ1, and protein aggregates might have a toxic effect on muscle fibers. The likely outcome is sarcomere destabilization, altered mechanotransduction and contraction, fiber necrosis and increased plasma CK. HyperCKaemia in this condition is common and sometimes the sole overt manifestation. It is possible that CASQ1 mutations may go undiagnosed, if a muscle biopsy is not taken, and that the condition is more frequent than supposed.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
