Abstract: The MATR3 protein was first identified comprising the nuclear matrix, an essential part of preserving the skeletal framework of the nucleus, amongst other nuclear matrins. Composed mainly of intrinsically disordered regions, the protein is made up of 847 amino acids, creating 4 distinct functional domains: two zinc-finger domains (ZF1 and ZF2) and two RNA-recognition motifs (RRM1 and RRM2,) as well as a highly acidic carboxy-terminal with histone-binding ability. This structural design allows MATR3 protein to interact with DNA and/or DNA/RNA-binding proteins, aiding in chromosomal and genomic integrity regulation, RNA-binding mediated post-transcriptional mRNA regulation, and nuclear lamina association to maintain nuclear framework. An autosomal dominant Ser85Cys (S85C) mutation in MATR3 was identified in a multigenerational family displaying vocal cord and pharyngeal weakness as well as distal and asymmetrical myopathy (Senderek et al., 2009). Intriguingly, a neurogenic or myopathic pattern was indicated by these patients neurophysiological and muscle biopsy-based examinations. They displayed several signs emblematic of upper motor neuron lesions such as a “split-hand” pattern, tongue fasciculations, brunt jaw-jerk, upper limb reflexes, and brisk knee. Due to this, S85C patients in three independent families were reassessed and found to suffer progressive respiratory failure leading to death 15 years after onset (Johnson et al., 2014), in contrast to the typical 2–5 years. This led to a recategorization of S85C-associated disorder to “slow progressive amytrophic lateral sclerosis (ALS) with distal myopathy,” and is approximated at 0.5% frequency of all mutations. Initially, 3 cohorts containing unique missense MATR3 mutations associated with ALS were characterized; Phe115Cys (F115C) and Thr622Ala (T622A) were found in familial ALS patients, and Pro154Ser (P154S) in a sporadic ALS patient (Johnson et al., 2014). Subsequently, 3 additional MATR3 mutations including p.Ser610Phe (Xu et al., 2016), a missense mutation found in ALS patients from Chinese origin with 3 variants (p.Ala313Gly, p.Arg147Lys, and p.Gln347Lys). Secondly, a duplication of exon 15 referred to as MATR3 Variant 5 (Castro et al., 2020) was found in a patient presenting symptoms of frontotemporal dementia, lastly, a heterozygous missense mutation called Ala72Thr was found in a Taiwanese ALS patient (Lin et al., 2015).