Thin filament proteins mutations associated with skeletal myopathies: defective regulation of muscle contraction.
In humans, more than 140 different mutations within seven genes (ACTA1, TPM2, TPM3, TNNI2, TNNT1, TNNT3, and NEB) that encode thin filament proteins (skeletal alpha-actin, beta-tropomyosin, gamma-tropomyosin, fast skeletal muscle troponin I, slow skeletal muscle troponin T, fast skeletal muscle troponin T, and nebulin, respectively) have been identified. These mutations have been linked to muscle weakness and various congenital skeletal myopathies including nemaline myopathy, distal arthrogryposis, cap disease, actin myopathy, congenital fiber type disproportion, rod-core myopathy, intranuclear rod myopathy, and distal myopathy, with a dramatic negative impact on the quality of life. In this review, we discuss studies that use various approaches such as patient biopsy specimen samples, tissue culture systems or transgenic animal models, and that demonstrate how thin filament proteins mutations alter muscle structure and contractile function. With an enhanced understanding of the cellular and molecular mechanisms underlying muscle weakness in patients carrying such mutations, better therapy strategies can be developed to improve the quality of life.
Ochala
Julien
J
Department of Neuroscience, Clinical Neurophysiology, University Hospital, Entrance 85, SE-751 85, Uppsala, Sweden. julien.ochala@neurofys.uu.se
D000199:Actins / Q000235:genetics*; D000818:Animals; D006801:Humans; D009119:Muscle Contraction; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000503:physiopathology*; D009135:Muscular Diseases / Q000151:congenital / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D020107:Troponin T / Q000235:genetics*
D000199:Actins; D009124:Muscle Proteins; D020107:Troponin T; C035620:nebulin