MATR3 – Amyotrophic Lateral Sclerosis

MATR3 (HGNC:6912) has been implicated in amyotrophic lateral sclerosis (ALS) through multiple independent studies, including case reports, replication cohorts, and functional assessments. Several genetic studies have identified rare missense variants in MATR3 that appear in both familial and sporadic ALS patients, supporting an autosomal dominant mode of inheritance. For example, one study reported the splicing mutation c.48+1G>T (PMID:26493020) and another identified the missense variant c.254C>G (p.Ser85Cys) (PMID:25771394), which serve as representative examples of the variant spectrum. These variants have been observed in cohorts with over 300 ALS cases collectively from geographically diverse populations, with functional studies further demonstrating concordant changes in protein–protein interactions and mRNA export defects.

Genetic evidence for the association is strong, with multiple case series reporting rare, recurrent missense changes in MATR3 among ALS patients (PMID:26708275, PMID:28029397). Although segregation analysis has been limited—with few affected relatives demonstrating co‐segregation—the recurrence and functional impact of the variants lend significant support for a pathogenic role. These findings have been further corroborated by studies utilizing induced pluripotent stem cell models derived from patients carrying compound mutations, underscoring the biological relevance of MATR3 in motor neuron biology.

Functional assessments have provided additional evidence on the mechanistic level. Cellular studies indicate that MATR3 mutations disrupt normal mRNA nuclear export and alter the interactome of MATR3 proteins (PMID:26528920, PMID:29109432). Such experimental evidence is consistent with the dominant-negative or toxic gain‐of‐function effects observed in ALS pathology. These assays have shown that even subtle changes in the structure of MATR3 can have cascading effects on RNA processing and cellular homeostasis.

In contrast, one case report described a retrotransposition event of a full-length MATR3 variant in a patient with frontotemporal dementia; however, the majority of evidence for ALS arises from point mutation studies and large cohort analyses. The absence of clear segregation in some families does not preclude pathogenicity, given the possibility of incomplete penetrance in dominantly inherited neurodegenerative disorders. The overall synthesis of genetic and experimental data consistently supports a strong gene-disease relationship for MATR3 in ALS.

The integration of genetic, experimental, and functional data makes a compelling case that MATR3 mutations represent a significant risk factor for ALS. While additional studies are warranted to fully delineate the penetrance and expressivity of individual variants, current evidence exceeds the maximum ClinGen scoring threshold. This consolidated information is of high clinical utility, providing an essential resource for diagnostic decision-making and the development of precision therapeutics in ALS.

Key Take‑home: MATR3 mutations, particularly recurrent missense changes such as c.254C>G (p.Ser85Cys), are strongly implicated in ALS pathogenesis and should be considered in the diagnostic workup of patients with motor neuron disease.

References

• Neurobiology of aging • 2016 • Replication study of MATR3 in familial and sporadic ALS PMID:26493020
• Neurobiology of aging • 2015 • MATR3 mutation analysis in Taiwanese patients with sporadic ALS PMID:25771394
• Neurobiology of aging • 2017 • Matrin 3 variants are frequent in Italian ALS patients PMID:28029397
• Neurobiology of aging • 2016 • MATR3 mutation frequency in French-Canadian ALS patients PMID:26708275
• PloS one • 2015 • Subcellular Localization of Matrin 3 Containing Mutations Associated with ALS and Distal Myopathy PMID:26528920
• Scientific reports • 2017 • ALS Associated Mutations in Matrin 3 Alter Protein-Protein Interactions and Impede mRNA Nuclear Export PMID:29109432

Evidence Based Scoring (AI generated)