title: Mutations in mitochondrial ribosomal protein MRPL12 leads to growth retardation, neurological deterioration and mitochondrial translation deficiency.
abstract: Multiple respiratory chain deficiencies represent a common cause of mitochondrial diseases and are associated with a wide range of clinical symptoms. We report a subject, born to consanguineous parents, with growth retardation and neurological deterioration. Multiple respiratory chain deficiency was found in muscle and fibroblasts of the subject as well as abnormal assembly of complexes I and IV. A microsatellite genotyping of the family members detected only one region of homozygosity on chromosome 17q24.2-q25.3 in which we focused our attention to genes involved in mitochondrial translation. We sequenced MRPL12, encoding the mitochondrial ribosomal protein L12 and identified a c.542C>T transition in exon 5 changing a highly conserved alanine into a valine (p.Ala181Val). This mutation resulted in a decreased steady-state level of MRPL12 protein, with altered integration into the large ribosomal subunit. Moreover, an overall mitochondrial translation defect was observed in the subject's fibroblasts with a significant reduction of synthesis of COXI, COXII and COXIII subunits. Modeling of MRPL12 shows Ala181 positioned in a helix potentially involved in an interface of interaction suggesting that the p.Ala181Val change might be predicted to alter interactions with the elongation factors. These results contrast with the eubacterial orthologues of human MRPL12, where L7/L12 proteins do not appear to have a selective effect on translation. Therefore, analysis of the mutated version found in the subject presented here suggests that the mammalian protein does not function in an entirely analogous manner to the eubacterial L7/L12 equivalent.
authors.affiliation: Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine and INSERM U781, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France. serre@ijm.univ-paris-diderot.fr
authors.forename: Valérie
authors.initials: V
authors.lastname: Serre
authors.forename: Agata
authors.initials: A
authors.lastname: Rozanska
authors.forename: Marine
authors.initials: M
authors.lastname: Beinat
authors.forename: Dominique
authors.initials: D
authors.lastname: Chretien
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Agnès
authors.initials: A
authors.lastname: Rötig
authors.forename: Zofia M
authors.initials: ZM
authors.lastname: Chrzanowska-Lightowlers
mesh_terms: D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D002675:Child, Preschool; D005347:Fibroblasts / Q000378:metabolism; D005838:Genotype; D006130:Growth Disorders / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009422:Nervous System Diseases / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010441:Peptide Chain Elongation, Translational; D012269:Ribosomal Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D018797:Cell Cycle Proteins; C099418:MRPL12 protein, human; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D012269:Ribosomal Proteins