biostudies-literatureWeterman MAJNIAID NIH HHSNational Institutes of HealthNational Institute of General Medical SciencesNIGMS NIH HHS4036-4050https://www.ebi.ac.uk/biostudies/studies/S-EPMC6240730biostudies-literatureUnknown27(23)Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes implicated in several dominant and recessive disease phenotypes. The canonical function of ARSs is to couple an amino acid to a cognate transfer RNA (tRNA). We identified three novel disease-associated missense mutations in the alanyl-tRNA synthetase (AARS) gene in three families with dominant axonal Charcot-Marie-Tooth (CMT) disease. Two mutations (p.Arg326Trp and p.Glu337Lys) are located near a recurrent pathologic change in AARS, p.Arg329His. The third (p.Ser627Leu) is in the editing domain of the protein in which hitherto only mutations associated with recessive encephalopathies have been described. Yeast complementation assays demonstrated that two mutations (p.Ser627Leu and p.Arg326Trp) represent loss-of-function alHuman molecular geneticsHypermorphic and hypomorphic AARS alleles in patients with CMT2N expand clinical and molecular heterogeneities.PMC6240730GM1081602R01 GM114343R01 GM118647T32 GM007863GM118647T32 GM007315R01 AI139202GM007863Oprescu SGordillo SKenter SBKuo MTakase RHou YMWitteveen RJWBreuning MWeterman MAJKarjosukarso DWAntonellis ABaas Fvan Ruissen FBienfait HMEBronk MVerhamme Cde Visser MfalseHypermorphic and hypomorphic AARS alleles in patients with CMT2N expand clinical and molecular heterogeneities.Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes implicated in several dominant and recessive disease phenotypes. The canonical function of ARSs is to couple an amino acid to a cognate transfer RNA (tRNA). We identified three novel disease-associated missense mutations in the alanyl-tRNA synthetase (AARS) gene in three families with dominant axonal Charcot-Marie-Tooth (CMT) disease. Two mutations (p.Arg326Trp and p.Glu337Lys) are located near a recurrent pathologic change in AARS, p.Arg329His. The third (p.Ser627Leu) is in the editing domain of the protein in which hitherto only mutations associated with recessive encephalopathies have been described. Yeast complementation assays demonstrated that two mutations (p.Ser627Leu and p.Arg326Trp) represent loss-of-function al2018-01-01T00:00:00Z2018 Dec2026-07-16T01:38:17.743Z2021-03-12T08:07:59ZS-EPMC62407303012483010.1093/hmg/ddy290