Your browser doesn't support javascript.
loading
Mutations of the mitochondrial carrier translocase channel subunit TIM22 cause early-onset mitochondrial myopathy.
Pacheu-Grau, David; Callegari, Sylvie; Emperador, Sonia; Thompson, Kyle; Aich, Abhishek; Topol, Sarah E; Spencer, Emily G; McFarland, Robert; Ruiz-Pesini, Eduardo; Torkamani, Ali; Taylor, Robert W; Montoya, Julio; Rehling, Peter.
Afiliação
  • Pacheu-Grau D; Department of Cellular Biochemistry, University Medical Center Göttingen, Göttingen, D-37073, Germany.
  • Callegari S; Department of Cellular Biochemistry, University Medical Center Göttingen, Göttingen, D-37073, Germany.
  • Emperador S; Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza-CIBER de Enfermedades Raras (CIBERER)-Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, 50013, Spain.
  • Thompson K; Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom.
  • Aich A; Department of Cellular Biochemistry, University Medical Center Göttingen, Göttingen, D-37073, Germany.
  • Topol SE; The Scripps Translational Science Institute, The Scripps Research Institute, La Jolla, CA 92037, United States.
  • Spencer EG; The Scripps Translational Science Institute, The Scripps Research Institute, La Jolla, CA 92037, United States.
  • McFarland R; Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom.
  • Ruiz-Pesini E; Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza-CIBER de Enfermedades Raras (CIBERER)-Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, 50013, Spain.
  • Torkamani A; The Scripps Translational Science Institute, The Scripps Research Institute, La Jolla, CA 92037, United States.
  • Taylor RW; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, United States.
  • Montoya J; Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom.
  • Rehling P; Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza-CIBER de Enfermedades Raras (CIBERER)-Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, 50013, Spain.
Hum Mol Genet ; 27(23): 4135-4144, 2018 12 01.
Article em En | MEDLINE | ID: mdl-30452684
Protein import into mitochondria is facilitated by translocases within the outer and the inner mitochondrial membranes that are dedicated to a highly specific subset of client proteins. The mitochondrial carrier translocase (TIM22 complex) inserts multispanning proteins, such as mitochondrial metabolite carriers and translocase subunits (TIM23, TIM17A/B and TIM22), into the inner mitochondrial membrane. Both types of substrates are essential for mitochondrial metabolic function and biogenesis. Here, we report on a subject, diagnosed at 1.5 years, with a neuromuscular presentation, comprising hypotonia, gastroesophageal reflux disease and persistently elevated serum and Cerebrospinal fluid lactate (CSF). Patient fibroblasts displayed reduced oxidative capacity and altered mitochondrial morphology. Using trans-mitochondrial cybrid cell lines, we excluded a candidate variant in mitochondrial DNA as causative of these effects. Whole-exome sequencing identified compound heterozygous variants in the TIM22 gene (NM_013337), resulting in premature truncation in one allele (p.Tyr25Ter) and a point mutation in a conserved residue (p.Val33Leu), within the intermembrane space region, of the TIM22 protein in the second allele. Although mRNA transcripts of TIM22 were elevated, biochemical analyses revealed lower levels of TIM22 protein and an even greater deficiency of TIM22 complex formation. In agreement with a defect in carrier translocase function, carrier protein amounts in the inner membrane were found to be reduced. This is the first report of pathogenic variants in the TIM22 pore-forming subunit of the carrier translocase affecting the biogenesis of inner mitochondrial membrane proteins critical for metabolite exchange.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Transporte / Miopatias Mitocondriais / Proteínas de Transporte da Membrana Mitocondrial / Mitocôndrias Tipo de estudo: Prognostic_studies Limite: Child / Female / Humans Idioma: En Revista: Hum Mol Genet Assunto da revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Transporte / Miopatias Mitocondriais / Proteínas de Transporte da Membrana Mitocondrial / Mitocôndrias Tipo de estudo: Prognostic_studies Limite: Child / Female / Humans Idioma: En Revista: Hum Mol Genet Assunto da revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Alemanha