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Neurology. 2015 May 19;84(20):2040-7. doi: 10.1212/WNL.0000000000001583. Epub 2015 Apr 22.

A novel AARS mutation in a family with dominant myeloneuropathy.

Author information

1
From the Department of Neurology (W.W.M., S.S.S.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; the Cellular and Molecular Biology Program (L.B.G., A.A.), Medical Science Training Program (L.B.G.), and the Departments of Human Genetics (A.A.) and Neurology (A.A.), University of Michigan Medical School, Ann Arbor; the Neurogenetics Group (I.M., J.B., P.D.J.) and the Molecular Neurogenomics Group (E.D.V., A.J.), VIB, Department of Molecular Genetics, University of Antwerp; the Neurogenetics Laboratory (I.M., J.B., E.D.V., P.D.J., A.J.), Institute Born-Bunge, University of Antwerp; and the Department of Neurology (J.B., P.D.J.), Antwerp University Hospital, Belgium.
2
From the Department of Neurology (W.W.M., S.S.S.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; the Cellular and Molecular Biology Program (L.B.G., A.A.), Medical Science Training Program (L.B.G.), and the Departments of Human Genetics (A.A.) and Neurology (A.A.), University of Michigan Medical School, Ann Arbor; the Neurogenetics Group (I.M., J.B., P.D.J.) and the Molecular Neurogenomics Group (E.D.V., A.J.), VIB, Department of Molecular Genetics, University of Antwerp; the Neurogenetics Laboratory (I.M., J.B., E.D.V., P.D.J., A.J.), Institute Born-Bunge, University of Antwerp; and the Department of Neurology (J.B., P.D.J.), Antwerp University Hospital, Belgium. sscherer@mail.med.upenn.edu.

Abstract

OBJECTIVE:

To determine the genetic cause of neurodegeneration in a family with myeloneuropathy.

METHODS:

We studied 5 siblings in a family with a mild, dominantly inherited neuropathy by clinical examination and electrophysiology. One patient had a sural nerve biopsy. After ruling out common genetic causes of axonal Charcot-Marie-Tooth disease, we sequenced 3 tRNA synthetase genes associated with neuropathy.

RESULTS:

All affected family members had a mild axonal neuropathy, and 3 of 4 had lower extremity hyperreflexia, evidence of a superimposed myelopathy. A nerve biopsy showed evidence of chronic axonal loss. All affected family members had a heterozygous missense mutation c.304G>C (p.Gly102Arg) in the alanyl-tRNA synthetase (AARS) gene; this allele was not identified in unaffected individuals or control samples. The equivalent change in the yeast ortholog failed to complement a strain of yeast lacking AARS function, suggesting that the mutation is damaging.

CONCLUSION:

A novel mutation in AARS causes a mild myeloneuropathy, a novel phenotype for patients with mutations in one of the tRNA synthetase genes.

PMID:
25904691
PMCID:
PMC4442103
DOI:
10.1212/WNL.0000000000001583
[Indexed for MEDLINE]
Free PMC Article

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