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Neurology. 2014 Dec 2;83(23):2183-7. doi: 10.1212/WNL.0000000000001055. Epub 2014 Oct 31.

A homozygous splice-site mutation in CARS2 is associated with progressive myoclonic epilepsy.

Author information

1
From the Department of Epileptology and Life & Brain Center (K.H., G.Z., S.M.-H., C.E.E., W.S.K.), University of Bonn; Department of Neuropediatrics and Muscle Disorders (J.K., R.K.), University of Freiburg; Cologne Center for Genomics (A.-K.R., H.T., P.N., T.S.), Center for Molecular Medicine Cologne (P.N.), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (P.N.), University of Cologne, Germany; Genetic Department (O.O.), Institute of Experimental Medicine (DETAE), Istanbul University, Turkey; Department of Neurology and Epileptology (Y.W., F.B., H.L.), Hertie Institute for Clinical Brain Research, University of Tübingen, Germany.
2
From the Department of Epileptology and Life & Brain Center (K.H., G.Z., S.M.-H., C.E.E., W.S.K.), University of Bonn; Department of Neuropediatrics and Muscle Disorders (J.K., R.K.), University of Freiburg; Cologne Center for Genomics (A.-K.R., H.T., P.N., T.S.), Center for Molecular Medicine Cologne (P.N.), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (P.N.), University of Cologne, Germany; Genetic Department (O.O.), Institute of Experimental Medicine (DETAE), Istanbul University, Turkey; Department of Neurology and Epileptology (Y.W., F.B., H.L.), Hertie Institute for Clinical Brain Research, University of Tübingen, Germany. wolfram.kunz@ukb.uni-bonn.de.

Abstract

OBJECTIVE:

We report a consanguineous family with 2 affected individuals whose clinical symptoms closely resembled MERRF (myoclonus epilepsy with ragged red fibers) syndrome including severe myoclonic epilepsy, progressive spastic tetraparesis, progressive impairment of vision and hearing, as well as progressive cognitive decline.

METHODS:

After excluding the presence of pathogenic mitochondrial DNA mutations, whole-exome sequencing of blood DNA from the index patient was performed. Detected homozygous mutations and their cosegregation were confirmed by Sanger sequencing. CARS2 (cysteinyl-tRNA synthetase 2, mitochondrial) messenger RNA analysis was performed by reverse transcription PCR and sequencing.

RESULTS:

We identified a homozygous c.655G>A mutation in the CARS2 gene cosegregating in the family. The mutation is localized at the last nucleotide of exon 6 and thus is predicted to cause aberrant splicing. Analysis of the CARS2 messenger RNA showed that the presence of the mutation resulted in removal of exon 6. This leads to an in-frame deletion of 28 amino acids in a conserved sequence motif of the protein involved in stabilization of the acceptor end hairpin of tRNA(Cys).

CONCLUSION:

CARS2 is a novel disease gene associated with a severe progressive myoclonic epilepsy most resembling MERRF syndrome.

PMID:
25361775
DOI:
10.1212/WNL.0000000000001055
[Indexed for MEDLINE]

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