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Hum Mol Genet. 2018 Dec 1;27(23):4036-4050. doi: 10.1093/hmg/ddy290.

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

Author information

1
Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands.
2
Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI, USA.
3
Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI, USA.
4
Department of Clinical Genetics and Genome Analysis, Academic Medical Center, Amsterdam, Netherlands.
5
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, USA.
6
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.
7
Department of Neurology, Alrijne Hospital, Leiden, Netherlands.
8
Department of Neurology, Spaarne Gasthuis, Haarlem, Netherlands.
9
Department of Neurology, Academic Medical Center, Amsterdam, Netherlands.
10
Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, USA.

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 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 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 messenger RNA (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.

PMID:
30124830
PMCID:
PMC6240730
[Available on 2019-12-01]
DOI:
10.1093/hmg/ddy290
[Indexed for MEDLINE]

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