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EWSR1 – Amyotrophic Lateral Sclerosis

EWSR1 has been mutationally screened in cohorts of Amyotrophic Lateral Sclerosis patients, revealing 3 heterozygous missense variants (PMID:22454397) that were absent in large control groups. These variants occurred in unrelated sporadic cases with no reported segregation, consistent with an autosomal dominant pattern. The small number of probands and lack of co-segregation limits the genetic evidence under ClinGen criteria.

Functional assays demonstrate that ALS-associated EWSR1 variants disrupt nuclear localization and promote aggregation in vitro, confer neurodegeneration in Drosophila motor neurons, and exhibit cytoplasmic mislocalization in postmortem ALS tissue (PMID:22454397). Broader evidence implicates EWSR1 in central nervous system disorders including ALS and frontotemporal dementia, supporting a toxic gain-of-function mechanism (PMID:30481590). These concordant functional data meet a moderate level of experimental support according to ClinGen guidelines.

Key take-home: EWSR1 variants represent a limited but emerging genetic risk factor for ALS, with functional studies substantiating their pathogenic potential.

References

  • Human molecular genetics • 2012 • Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. PMID:22454397
  • Biochimica et biophysica acta. Molecular basis of disease • 2019 • EWSR1, a multifunctional protein, regulates cellular function and aging via genetic and epigenetic pathways. PMID:30481590

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Three heterozygous missense variants in unrelated ALS patients; no familial segregation; absent in controls

Genetic Evidence

Limited

Three missense variants in three unrelated sporadic cases; heterozygous; no segregation data; absent in large control cohorts ([PMID:22454397])

Functional Evidence

Moderate

In vitro aggregation and mislocalization assays, Drosophila neurodegeneration model, and postmortem cytoplasmic mislocalization support a toxic gain-of-function mechanism ([PMID:22454397]; [PMID:30481590])