title: Mitochondrial EFTs defects in juvenile-onset Leigh disease, ataxia, neuropathy, and optic atrophy.
abstract: OBJECTIVE
  We report novel defects of mitochondrial translation elongation factor Ts (EFTs), with high carrier frequency in Finland and expand the manifestations of this disease group from infantile cardiomyopathy to juvenile neuropathy/encephalopathy disorders.
  
  
  METHODS
  DNA analysis, whole-exome analysis, protein biochemistry, and protein modeling.
  
  
  RESULTS
  We used whole-exome sequencing to find the genetic cause of infantile-onset mitochondrial cardiomyopathy, progressing to juvenile-onset Leigh syndrome, neuropathy, and optic atrophy in 2 siblings. We found novel compound heterozygous mutations, c.944G>A [p.C315Y] and c.856C>T [p.Q286X], in the TSFM gene encoding mitochondrial EFTs. The same p.Q286X variant was found as compound heterozygous with a splice site change in a patient from a second family, with juvenile-onset optic atrophy, peripheral neuropathy, and ataxia. Our molecular modeling predicted the coding-region mutations to cause protein instability, which was experimentally confirmed in cultured patient cells, with mitochondrial translation defect and lacking EFTs. Only a single TSFM mutation has been previously described in different populations, leading to an infantile fatal multisystem disorder with cardiomyopathy. Sequence data from 35,000 Finnish population controls indicated that the heterozygous carrier frequency of p.Q286X change was exceptionally high in Finland, 1:80, but no homozygotes were found in the population, in our mitochondrial disease patient collection, or in an intrauterine fetal death material, suggesting early developmental lethality of the homozygotes.
  
  
  CONCLUSIONS
  We show that in addition to early-onset cardiomyopathy, TSFM mutations should be considered in childhood and juvenile encephalopathies with optic and/or peripheral neuropathy, ataxia, or Leigh disease.
authors.affiliation: From the Research Programs Unit, Molecular Neurology, Biomedicum Helsinki (S.A., P.I., L.E., V.B., H.T., A.S.), Institute for Molecular Medicine Finland (A.P.), Department of Medical Genetics, Haartman Institute (H.T.), and Neuroscience Center (A.S.), University of Helsinki; Department of Child Neurology, Children's Hospital (P.I., H.P., T. Lönnqvist), and Department of Neurology (A.S.), Helsinki University Central Hospital, Finland; Analytic and Translational Genetics Unit, Department of Medicine (A.P.), and Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry (A.P.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics (A.P.), Broad Institute of MIT and Harvard, Cambridge, MA; and Department of Pathology (T. Lehtonen, J.L.), University of Turku, Finland.
authors.forename: Sofia
authors.initials: S
authors.lastname: Ahola
authors.affiliation: From the Research Programs Unit, Molecular Neurology, Biomedicum Helsinki (S.A., P.I., L.E., V.B., H.T., A.S.), Institute for Molecular Medicine Finland (A.P.), Department of Medical Genetics, Haartman Institute (H.T.), and Neuroscience Center (A.S.), University of Helsinki; Department of Child Neurology, Children's Hospital (P.I., H.P., T. Lönnqvist), and Department of Neurology (A.S.), Helsinki University Central Hospital, Finland; Analytic and Translational Genetics Unit, Department of Medicine (A.P.), and Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry (A.P.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics (A.P.), Broad Institute of MIT and Harvard, Cambridge, MA; and Department of Pathology (T. Lehtonen, J.L.), University of Turku, Finland.
authors.forename: Pirjo
authors.initials: P
authors.lastname: Isohanni
authors.affiliation: From the Research Programs Unit, Molecular Neurology, Biomedicum Helsinki (S.A., P.I., L.E., V.B., H.T., A.S.), Institute for Molecular Medicine Finland (A.P.), Department of Medical Genetics, Haartman Institute (H.T.), and Neuroscience Center (A.S.), University of Helsinki; Department of Child Neurology, Children's Hospital (P.I., H.P., T. Lönnqvist), and Department of Neurology (A.S.), Helsinki University Central Hospital, Finland; Analytic and Translational Genetics Unit, Department of Medicine (A.P.), and Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry (A.P.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics (A.P.), Broad Institute of MIT and Harvard, Cambridge, MA; and Department of Pathology (T. Lehtonen, J.L.), University of Turku, Finland.
authors.forename: Liliya
authors.initials: L
authors.lastname: Euro
authors.affiliation: From the Research Programs Unit, Molecular Neurology, Biomedicum Helsinki (S.A., P.I., L.E., V.B., H.T., A.S.), Institute for Molecular Medicine Finland (A.P.), Department of Medical Genetics, Haartman Institute (H.T.), and Neuroscience Center (A.S.), University of Helsinki; Department of Child Neurology, Children's Hospital (P.I., H.P., T. Lönnqvist), and Department of Neurology (A.S.), Helsinki University Central Hospital, Finland; Analytic and Translational Genetics Unit, Department of Medicine (A.P.), and Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry (A.P.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics (A.P.), Broad Institute of MIT and Harvard, Cambridge, MA; and Department of Pathology (T. Lehtonen, J.L.), University of Turku, Finland.
authors.forename: Virginia
authors.initials: V
authors.lastname: Brilhante
authors.affiliation: From the Research Programs Unit, Molecular Neurology, Biomedicum Helsinki (S.A., P.I., L.E., V.B., H.T., A.S.), Institute for Molecular Medicine Finland (A.P.), Department of Medical Genetics, Haartman Institute (H.T.), and Neuroscience Center (A.S.), University of Helsinki; Department of Child Neurology, Children's Hospital (P.I., H.P., T. Lönnqvist), and Department of Neurology (A.S.), Helsinki University Central Hospital, Finland; Analytic and Translational Genetics Unit, Department of Medicine (A.P.), and Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry (A.P.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics (A.P.), Broad Institute of MIT and Harvard, Cambridge, MA; and Department of Pathology (T. Lehtonen, J.L.), University of Turku, Finland.
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.affiliation: From the Research Programs Unit, Molecular Neurology, Biomedicum Helsinki (S.A., P.I., L.E., V.B., H.T., A.S.), Institute for Molecular Medicine Finland (A.P.), Department of Medical Genetics, Haartman Institute (H.T.), and Neuroscience Center (A.S.), University of Helsinki; Department of Child Neurology, Children's Hospital (P.I., H.P., T. Lönnqvist), and Department of Neurology (A.S.), Helsinki University Central Hospital, Finland; Analytic and Translational Genetics Unit, Department of Medicine (A.P.), and Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry (A.P.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics (A.P.), Broad Institute of MIT and Harvard, Cambridge, MA; and Department of Pathology (T. Lehtonen, J.L.), University of Turku, Finland.
authors.forename: Helena
authors.initials: H
authors.lastname: Pihko
authors.affiliation: From the Research Programs Unit, Molecular Neurology, Biomedicum Helsinki (S.A., P.I., L.E., V.B., H.T., A.S.), Institute for Molecular Medicine Finland (A.P.), Department of Medical Genetics, Haartman Institute (H.T.), and Neuroscience Center (A.S.), University of Helsinki; Department of Child Neurology, Children's Hospital (P.I., H.P., T. Lönnqvist), and Department of Neurology (A.S.), Helsinki University Central Hospital, Finland; Analytic and Translational Genetics Unit, Department of Medicine (A.P.), and Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry (A.P.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics (A.P.), Broad Institute of MIT and Harvard, Cambridge, MA; and Department of Pathology (T. Lehtonen, J.L.), University of Turku, Finland.
authors.forename: Tuula
authors.initials: T
authors.lastname: Lönnqvist
authors.affiliation: From the Research Programs Unit, Molecular Neurology, Biomedicum Helsinki (S.A., P.I., L.E., V.B., H.T., A.S.), Institute for Molecular Medicine Finland (A.P.), Department of Medical Genetics, Haartman Institute (H.T.), and Neuroscience Center (A.S.), University of Helsinki; Department of Child Neurology, Children's Hospital (P.I., H.P., T. Lönnqvist), and Department of Neurology (A.S.), Helsinki University Central Hospital, Finland; Analytic and Translational Genetics Unit, Department of Medicine (A.P.), and Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry (A.P.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics (A.P.), Broad Institute of MIT and Harvard, Cambridge, MA; and Department of Pathology (T. Lehtonen, J.L.), University of Turku, Finland.
authors.forename: Tanita
authors.initials: T
authors.lastname: Lehtonen
authors.affiliation: From the Research Programs Unit, Molecular Neurology, Biomedicum Helsinki (S.A., P.I., L.E., V.B., H.T., A.S.), Institute for Molecular Medicine Finland (A.P.), Department of Medical Genetics, Haartman Institute (H.T.), and Neuroscience Center (A.S.), University of Helsinki; Department of Child Neurology, Children's Hospital (P.I., H.P., T. Lönnqvist), and Department of Neurology (A.S.), Helsinki University Central Hospital, Finland; Analytic and Translational Genetics Unit, Department of Medicine (A.P.), and Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry (A.P.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics (A.P.), Broad Institute of MIT and Harvard, Cambridge, MA; and Department of Pathology (T. Lehtonen, J.L.), University of Turku, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Laine
authors.affiliation: From the Research Programs Unit, Molecular Neurology, Biomedicum Helsinki (S.A., P.I., L.E., V.B., H.T., A.S.), Institute for Molecular Medicine Finland (A.P.), Department of Medical Genetics, Haartman Institute (H.T.), and Neuroscience Center (A.S.), University of Helsinki; Department of Child Neurology, Children's Hospital (P.I., H.P., T. Lönnqvist), and Department of Neurology (A.S.), Helsinki University Central Hospital, Finland; Analytic and Translational Genetics Unit, Department of Medicine (A.P.), and Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry (A.P.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics (A.P.), Broad Institute of MIT and Harvard, Cambridge, MA; and Department of Pathology (T. Lehtonen, J.L.), University of Turku, Finland.
authors.forename: Henna
authors.initials: H
authors.lastname: Tyynismaa
authors.affiliation: From the Research Programs Unit, Molecular Neurology, Biomedicum Helsinki (S.A., P.I., L.E., V.B., H.T., A.S.), Institute for Molecular Medicine Finland (A.P.), Department of Medical Genetics, Haartman Institute (H.T.), and Neuroscience Center (A.S.), University of Helsinki; Department of Child Neurology, Children's Hospital (P.I., H.P., T. Lönnqvist), and Department of Neurology (A.S.), Helsinki University Central Hospital, Finland; Analytic and Translational Genetics Unit, Department of Medicine (A.P.), and Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry (A.P.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics (A.P.), Broad Institute of MIT and Harvard, Cambridge, MA; and Department of Pathology (T. Lehtonen, J.L.), University of Turku, Finland. anu.wartiovaara@helsinki.fi.
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
mesh_terms: D000293:Adolescent; D001259:Ataxia / Q000175:diagnosis / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D005387:Finland; D006801:Humans; D007888:Leigh Disease / Q000175:diagnosis / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009896:Optic Atrophy / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D010445:Peptide Elongation Factors / Q000235:genetics*; D010641:Phenotype; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial; D010445:Peptide Elongation Factors; C023512:elongation factor Ts