![]() Dt mice have been reported to display muscle weakness and skeletal muscle cytoarchitecture instability ( Dalpé et al., 1999). ![]() The Dst gene was identified as a causative gene in dt mice ( Brown et al., 1995 Guo et al., 1995), and later, dt mice were used as mouse models of HSAN-VI ( Ferrier et al., 2014). Thus, the impact of DST-b deficiency in skeletal and cardiac muscles on the manifestations of HSAN-VI patients has not been fully elucidated.ĭystonia musculorum ( dt) is a spontaneously occurring mutant in mice ( Duchen et al., 1964 Horie et al., 2016) that results in sensory neuron degeneration, retarded body growth, dystonic and ataxic movements, and early postnatal lethality. Because all reported HSAN-VI mutations could disrupt both DST-a and DST-b, it is unknown whether these muscle manifestations are caused by cell-autonomous effects of DST-b mutation and/or secondary effects of neurological abnormalities caused by DST-a mutation. HSAN-VI patients exhibit muscular and cardiac abnormalities, such as reduced muscular action potential amplitude, muscle weakness, and disrupted cardiovascular reflexes ( Edvardson et al., 2012 Manganelli et al., 2017 Fortugno et al., 2019 Jin et al., 2020 Motley et al., 2020). DST-a is considered the crucial DST isoform in the pathogenesis of HSAN-VI because it is a neural isoform, and transgenic expression of Dst-a2 under the control of a neuronal promoter partially rescues disease phenotypes of Dst Tg4 homozygous mice, which is a mouse model of HSAN-VI ( Ferrier et al., 2014). Loss-of-function mutations in the DST locus have been reported to cause neurological disorders, hereditary sensory and autonomic neuropathy type 6 (HSAN-VI) ( Edvardson et al., 2012), and the skin blistering disease epidermolysis bullosa simplex ( Groves et al., 2010). Although DST-a and DST-b share most of the same exons, DST-b contains five additional isoform-specific exons. At least three major DST isoforms exist, DST-a, DST-b, and DST-e, which are predominantly expressed in neural, muscular, and epidermal tissues, respectively ( Leung et al., 2001). The DST gene consists of over 100 exons and generates tissue-selective protein isoforms through alternative splicing and different transcription initiation sites. Dystonin (DST), also called bullous pemphigoid antigen 1 (BPAG1), is a cytoskeletal linker protein that belongs to the plakin family, which consists of DST, plectin, microtubule actin cross-linking factor 1 (MACF1), desmoplakin, and other plakins ( Boyer et al., 2010a Künzli et al., 2016 Horie et al., 2017). Skeletal and cardiac striated muscle fibers consist of a complex cytoskeletal architecture, and maintenance of the sarcomere structure is essential for muscle contraction. Here, we demonstrate that the Dst-b isoform is essential for long-term maintenance of striated muscles. In silico analysis identified DST-b alleles with nonsense mutations in populations worldwide, suggesting that some unidentified hereditary myopathy and cardiomyopathy are caused by DST-b mutations. RNA-sequencing analysis revealed changes in expression of genes responsible for cardiovascular functions. We also found nuclear inclusions containing p62, ubiquitin, and SUMO proteins with nuclear envelope invaginations as a unique pathological hallmark in Dst-b mutation-induced cardiomyopathy. We observed desmin aggregation, focal myofibrillar dissolution, and mitochondrial accumulation in striated muscles, which are common characteristics of myofibrillar myopathy. Dst-b mutant mice exhibited late-onset protein aggregate myopathy and cardiomyopathy without neuropathy. ![]() To investigate the specific function of DST-b in striated muscles, we generated a Dst-b-specific mutant mouse model harboring a nonsense mutation. Because DST-b contains all of the DST-a-encoding exons, known HSAN-VI mutations could affect both DST-a and DST-b isoforms. DST mutations cause different disorders, including hereditary sensory and autonomic neuropathy 6 (HSAN-VI) and epidermolysis bullosa simplex however, etiology of the muscle phenotype in DST-related diseases has been unclear. Dystonin ( DST), which encodes cytoskeletal linker proteins, expresses three tissue-selective isoforms: neural DST-a, muscular DST-b, and epithelial DST-e.
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