Abstract
Mutations in MATR3 have been associated with amyotrophic lateral sclerosis (ALS) as well as a form of distal myopathy termed vocal cord pharyngeal distal myopathy (VCPDM). To begin to understand how mutations in MATR3 may cause disease, here we provide initial characterization of transgenic (Tg) mice expressing human wild-type (WT) MATR3 (MATR3WT) and ALS-mutant F115C MATR3 (MATR3F115C) proteins under the control of the mouse prion promoter (MoPrP). For each construct, we established multiple independent lines of mice that stably transmitted the transgene. Unexpectedly, for all stably-transmitting lines examined, MATR3 transgenic mRNA expression was more robust in muscle, with minimal expression in spinal cord. The levels of transgenic mRNA in muscle did not differ between mice from our lead MATR3F115C line and lead MATR3WT line, but mice from the lead MATR3F115C line had significantly higher levels of MATR3 protein in muscle over the lead MATR3WT line. Mice from the three independent, established lines of MATR3F115C mice developed weakness in both fore- and hind-limbs as early as < 1 months of age; whereas, MATR3WT mice aged to > 20 months were not overtly distinguishable from non-transgenic (NT) littermates based on basic motor phenotype. Muscle of both MATR3WT and MATR3F115C mice showed vacuoles by 2 months of age which worsened by ~ 10 months, but vacuolation was noticeably more severe in MATR3F115C mice. Overall, our results indicate that increasing the levels of MATR3 in muscle can cause pathologic changes associated with myopathy, with MATR3F115C expression causing overt muscle atrophy and a profound motor phenotype. The findings suggest that analysis of muscle pathology in individuals harboring ALS-linked MATR3 mutations should be routinely considered.
Highlights
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting both upper and lower motor neurons leading to progressive paresis and paralysis, with death occurring between three to five years from the diagnosis [18]
Mutant matrin 3 (MATR3) (S85C) had been previously associated with an autosomal dominant distal myopathy with vocal cord and pharyngeal weakness (VCPDM) [5, 19]; in 2014, three different mutations (F115C, P154S, or T622A) in MATR3 were identified in cases of both family members (fALS) and sALS [7]
In an effort to determine the natural regulation of MATR3 in the body, we previously found that murine MATR3 expression decreased with age from postnatal day 1 through 2 months of age in the central nervous system (CNS) [15]
Summary
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting both upper and lower motor neurons leading to progressive paresis and paralysis, with death occurring between three to five years from the diagnosis [18]. Mutant MATR3 (S85C) had been previously associated with an autosomal dominant distal myopathy with vocal cord and pharyngeal weakness (VCPDM) [5, 19]; in 2014, three different mutations (F115C, P154S, or T622A) in MATR3 were identified in cases of both fALS and sALS [7]. Patients harboring the S85C mutation in MATR3 initially present with myopathy in the muscles of the hands and feet [5, 19] and have a slowly progressing disease that leads to respiratory. Patients carrying the F115C mutation in MATR3 develop dysarthria, dysphagia, weakness and variable degrees of dementia, with a typical course of 5 years before death [7]. Subsequent to the identification of ALS-linked MATR3 mutations, Johnson and colleagues reclassified the original VCPDM S85C cases as ALS [7]; there have been additional families with the S85C mutation that have been diagnosed with VCPDM, without indication of ALS [2, 12, 13, 19, 26], highlighting our lack of understanding of which disease(s) MATR3 mutations cause
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