Submission Details

Variants in MATR3 were first reported as a cause of autosomal dominant distal myopathy with vocal cord weakness in 2009 (Senderek J, et al., 2009, PMID: 19344878). The MATR3 gene encodes matrin-3, a highly conserved nuclear matrix protein that binds and interacts with nucleic acids (Belgrader et al., 1991; Hibino et al., 2006). It plays a role in RNA transcription and processing, as well as mRNA stabilization (Hibino et al., 2006). Structurally, the protein includes two zinc finger domains that interact with DNA, along with two domains that bind RNA (Belgrader et al., 1991; Hibino et al., 2006; Salton et al., 2011; Johnson et al., 2014). Heterozygous variants in the MATR3 gene are asserted to casue amyotrophic lateral sclerosis (ALS) type 21 and distal myopathy with vocal cord and pharyngeal weakness (VCPDM) inherited in an autosomal dominant manner (Senderek et al., 2009; Johnson et al., 2014); the ALS GCEP has lumped these into a single curation for distal myopathy based on an overlap of phenotypes and molecular mechanism. Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. At least 12 missense variants have been reported in 20 probands from 17 publications (PMIDs: 24686783, 28029397, 26493020, 25771394, 26199109, 26708275, 31432357, 31475037, 19344878, 25154462, 25185957, 25952333, 32361838, 29628183, 34659085, 35812165, 39192891). The Ser85Cys variant is recurrent and predominantly found in patients with distal myopathy, however one family was retrospectively diagnose with ALS (PMID: 24686783). Segregation of this variant across 39 patients from 5 families was included in this curation. Experimentally, this gene-disease relationship is supported by the role of MATR3 as an RNA-binding protein involved in mRNA transport and nuclear export, processes known to be impacted in ALS (PMID: 29109432). Additionally, MATR3 has been found to bind and interact with critical ALS proteins TDP-43 (PMID: 24686783, 29109432), FUS (PMID: 29109432) and C9orf92 (PMID: 33129345). Further support is provided by a mouse models including overexpression and CRISPR-cas9 knock-in models (PMID: 33082323) that partially recapitulates phenotypic and pathological features. In summary, there is definitive evidence to support the relationship between MATR3 and autosomal dominant distal myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.