CMT-NARS1

NARS1 | 2024

What Is CMT-NARS1?

CMT-NARS1 is a type of CMT caused by autosomal dominant mutations in the NARS1 gene. This gene provides instructions for making asparaginyl-tRNA synthetase, an enzyme that attaches the amino acid asparagine to its transfer RNA during protein synthesis. Mutations in the NARS1 gene disrupt this function, leading to impaired nerve signal transmission.

CMT-NARS1 is autosomal dominant, meaning that just one of the gene’s two copies needs a mutation to cause this subtype.

Clinical Features

The age of symptom onset in CMT-NARS1 is variable, ranging from childhood to adulthood. Symptoms typically begin in the lower extremities and progress over time to involve the upper limbs. Nerve conduction studies usually show somewhat slowed conduction velocities and reduced amplitudes, consistent with an axonal form of CMT.

CMT-NARS1 symptoms may include:

  • Weakness in the feet and lower legs
  • Muscle atrophy
  • Foot drop
  • Reduced or absent reflexes
  • Reduced sensation
  • A steppage-style walking pattern
  • Foot deformities, including high arches, and hammertoes (clawed toes)
  • Progressive involvement of the hands and forearms
  • Difficulty with fine motor skills and manual dexterity
  • Additional symptoms not listed here

Disease Course

CMT-NARS1 shows wide variability in severity and progression. Some individuals are mildly affected, while others develop a more severe disease. Disease progression is generally slow, and life expectancy is not reduced.

Clinical Basics

Subtype
CMT-NARS1

Classification
Unclassified Subtypes

Neuropathy Type
Axonal

Inheritance Pattern
autosomal dominant

Genetic Context

HGNC-Approved Gene Symbol
NARS1

Gene Full Name
Asparaginyl-tRNA Synthetase 1

HGNC Gene Alias(es)
ASNRS, NARS

Chromosome
18q21.31

Zygosity of Responsible Variant
Heterozygous

Variant Mechanism

Dominant-Negative

Details

Mechanistic basis:
Dominant-negative

Confidence:
Medium

Prediction:
The literature predicts a dominant-negative mechanism for CMT-NARS1: the heterozygous variants are catalytically null or hypomorphic for asparaginyl-tRNA aminoacylation yet cause dominant CMT, and 2025 functional studies show the mutant subunit disrupts the wild-type NARS1 homodimer, so added wild-type is not predicted to rescue. Biallelic true loss instead causes a distinct neurodevelopmental disorder, and a toxic gain-of-function alternative in the aaRS field holds confidence at medium.

Rationale:
The dominant CMT-NARS1 variants are catalytically compromised subunits that disrupt the wild-type NARS1 homodimer, directly supported by two 2025 studies, so added wild-type is not predicted to rescue: a dominant-negative effect, distinct from the biallelic neurodevelopmental disorder. A residual aaRS toxic-gain debate holds confidence at medium.

ClinVar Pathogenic Variants

View CMT-NARS1 ClinVar Variants

NARS1 OMIM Entry

NARS1 OMIM

More Info

CMT-NARS1 Research Opportunity

CMT Natural History Study

Original Discovery Publication

Publication Title

Dominant NARS1 mutations causing axonal Charcot-Marie-tooth disease expand NARS1-associated diseases

Authors

Beijer, D., Marte, S., Li, J. C., De Ridder, W., Chen, J. Z., Tadenev, A., L. D., Miers, K. E., Deconinck, T., Macdonell, R., Marques Jr, W., De Jonghe, P., Pratt, S. L., Meyer-Schuman, R., Züchner, S., Antonellis, A., Burgess, R. W., Baets, J.

Publication Date
March 8, 2024

DOI
10.1093/braincomms/fcae070

Updated: July 18, 2026 | By: K. Raymond

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