Comprehensive assessment of recessive, pathogenic alleles in a humanized yeast model reveals loss-of-function and dominant-negative effects.

Alanyl-tRNA synthetase 1 () encodes the enzyme that ligates tRNA molecules to alanine in the cytoplasm, which is required for protein translation. Variants in have been implicated in early-onset, multi-system recessive phenotypes and in later-onset dominant peripheral neuropathy; to date, no single variant has been associated with both dominant and recessive diseases raising questions about shared mechanisms between the two inheritance patterns. variants associated with recessive disease are predicted to result in null or hypomorphic alleles and this has been demonstrated, in part, via yeast complementation assays.

A model organism pipeline provides insight into the clinical heterogeneity of TARS1 loss-of-function variants.

Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed, essential enzymes that complete the first step of protein translation: ligation of amino acids to cognate tRNAs. Genes encoding ARSs have been implicated in myriad dominant and recessive phenotypes, the latter often affecting multiple tissues but with frequent involvement of the central and peripheral nervous systems, liver, and lungs. Threonyl-tRNA synthetase (TARS1) encodes the enzyme that ligates threonine to tRNA in the cytoplasm.

A previously unreported NARS1 variant causes dominant distal hereditary motor neuropathy in a French family.

Background And Aims: Pathogenic variants in the NARS1 gene, which encodes for the asparaginyl-tRNA synthetase1 (NARS1) enzyme, were associated with complex central and peripheral nervous system phenotypes. Recently, Charcot-Marie-Tooth (CMT) disease has been linked to heterozygous pathogenic variants in NARS1 in nine patients. Here, we report two brothers and their mother from a French family with distal hereditary motor neuropathy (dHMN) carrying a previously unreported NARS1 variant.

Dominant mutations causing axonal Charcot-Marie-Tooth disease expand -associated diseases.

Pathogenic variants in six aminoacyl-tRNA synthetase (ARS) genes are implicated in neurological disorders, most notably inherited peripheral neuropathies. ARSs are enzymes that charge tRNA molecules with cognate amino acids. Pathogenic variants in asparaginyl-tRNA synthetase () cause a neurological phenotype combining developmental delay, ataxia and demyelinating peripheral neuropathy.