WARS1 – Distal hereditary motor neuropathy

The autosomal dominant WARS1 gene encodes tryptophanyl-tRNA synthetase, which charges tRNA with tryptophan and exhibits non-canonical angiostatic functions. Pathogenic variants in WARS1 are associated with distal hereditary motor neuropathy, a group of inherited neuropathies marked by progressive distal limb muscle weakness and motor axon degeneration.

In a Taiwanese family with autosomal dominant dHMN, exome sequencing identified a heterozygous missense variant c.770A>G (p.His257Arg) in WARS1 that co-segregates with disease in two affected members and is absent in unaffected relatives ([PMID:28369220]). The same variant recurred in an independent Taiwanese pedigree and a Belgian family, demonstrating allelic recurrence across ancestries.

A separate mainland Chinese dHMN pedigree harbors a novel heterozygous variant c.941A>G (p.Asp314Gly) that completely co-segregates with disease in five affected individuals over three generations ([PMID:31069783]).

Collectively, at least nine affected relatives in three unrelated pedigrees support an autosomal dominant inheritance for WARS1-related dHMN and fulfill criteria for strong genetic evidence.

Functional assays of the p.His257Arg TrpRS variant demonstrate a dominant-negative effect on aminoacylation activity, compromised protein synthesis, reduced cell viability, neurite degeneration in neuronal models, and potentiation of angiostatic activity through enhanced interaction with vascular endothelial-cadherin ([PMID:28369220]).

These genetic and experimental data establish WARS1 as a strong cause of autosomal dominant dHMN, supporting inclusion of WARS1 in diagnostic gene panels for hereditary motor neuropathies. Key take-home: WARS1 variant testing informs definitive diagnosis, genotype-driven management, and future therapeutic development.

References

• Brain : a journal of neurology • 2017 • A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy. PMID:28369220
• Clinical genetics • 2019 • A novel WARS mutation (p.Asp314Gly) identified in a Chinese distal hereditary motor neuropathy family. PMID:31069783

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