title: A homozygous splice-site mutation in CARS2 is associated with progressive myoclonic epilepsy.
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).
  
  
  CONCLUSIONS
  CARS2 is a novel disease gene associated with a severe progressive myoclonic epilepsy most resembling MERRF syndrome.
authors.affiliation: 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.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hallmann
authors.affiliation: 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.
authors.forename: Gábor
authors.initials: G
authors.lastname: Zsurka
authors.affiliation: 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.
authors.forename: Susanna
authors.initials: S
authors.lastname: Moskau-Hartmann
authors.affiliation: 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.
authors.forename: Janbernd
authors.initials: J
authors.lastname: Kirschner
authors.affiliation: 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.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Korinthenberg
authors.affiliation: 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.
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Ruppert
authors.affiliation: 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.
authors.forename: Ozkan
authors.initials: O
authors.lastname: Ozdemir
authors.affiliation: 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.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Weber
authors.affiliation: 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.
authors.forename: Felicitas
authors.initials: F
authors.lastname: Becker
authors.affiliation: 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.
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
authors.affiliation: 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.
authors.forename: Christian E
authors.initials: CE
authors.lastname: Elger
authors.affiliation: 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.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sander
authors.affiliation: 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.
authors.forename: Wolfram S
authors.initials: WS
authors.lastname: Kunz
mesh_terms: D000328:Adult; D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics; D004831:Epilepsies, Myoclonic / Q000209:etiology / Q000235:genetics*; D005260:Female; D006720:Homozygote; D006801:Humans; D017243:MERRF Syndrome / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008928:Mitochondria / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D012326:RNA Splicing / Q000235:genetics; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial; D000604:Amino Acyl-tRNA Synthetases; C000595892:CARS2 protein, human