PUBLICATION

Hypermorphic and hypomorphic AARS alleles in patients with CMT2N expand clinical and molecular heterogeneities

Authors
Weterman, M.A.J., Kuo, M., Kenter, S.B., Gordillo, S., Karjosukarso, D.W., Takase, R., Bronk, M., Oprescu, S., Ruissen, F., Witteveen, R.J.W., Bienfait, H.M.E., Breuning, M., Verhamme, C., Hou, Y.M., Visser, M., Antonellis, A., Baas, F.
ID
ZDB-PUB-180821-6
Date
2018
Source
Human molecular genetics   27(23): 4036-4050 (Journal)
Registered Authors
Baas, Frank, Karjosukarso, Dyah
Keywords
none
MeSH Terms
  • Adult
  • Alanine-tRNA Ligase/genetics*
  • Alleles
  • Amino Acids/genetics
  • Amino Acyl-tRNA Synthetases/genetics*
  • Animals
  • Charcot-Marie-Tooth Disease/genetics*
  • Charcot-Marie-Tooth Disease/pathology
  • Female
  • Gene Expression Regulation, Enzymologic/genetics
  • Genetic Heterogeneity
  • Humans
  • Male
  • Middle Aged
  • Mutation/genetics
  • Pedigree
  • RNA, Transfer/genetics*
  • Yeasts/genetics
  • Zebrafish/genetics
PubMed
30124830 Full text @ Hum. Mol. Genet.
Abstract
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 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 alleles, while the third (p.Glu337Lys) represents a hypermorphic allele. Further, aminoacylation assays confirmed that the third mutation (p.Glu337Lys) increases tRNA charging velocity. To test the effect of each mutation in the context of a vertebrate nervous system, we developed a zebrafish assay. Remarkably, all three mutations caused a pathological phenotype of neural abnormalities when expressed in zebrafish, while expression of the human wild-type mRNA did not. Our data indicate that not only functional null or hypomorphic alleles, but also hypermorphic AARS alleles can cause dominantly inherited axonal CMT disease.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes