Mutations in mitochondrial ribosomal protein MRPL12 leads to growth retardation, neurological deterioration and mitochondrial translation deficiency

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1832

Article

Serre, Valerie^1,2  Rozanska, Agata⁴  Beinat, Marine^1,2  Chretien, Dominique^1,2  Boddaert, Nathalie^1,2  Munnich, Arnold^1,2  Roetig, Agnes^1,2,3  Chrzanowska-Lightowlers, Zofia M.⁴ 

[1] Univ Paris Descartes Sorbonne Paris Cite, Inst Imagine, F-75015 Paris, France

[2] Hop Necker Enfants Malad, INSERM U781, F-75015 Paris, France

[3] Hop Necker Enfants Malad, Dept Pediat, F-75015 Paris, France

[4] Newcastle Univ, Sch Med, Inst Ageing & Hlth, Wellcome Trust Ctr Mitochondrial Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

关键词: Mitochondria;    Mitoribosome;    Protein synthesis;    Disease;    OXPHOS defect;   

DOI  :  10.1016/j.bbadis.2013.04.014

来源: Elsevier

【 摘 要 】

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 land IV. A microsatellite genotyping of the family members detected only one region of homozygosity on chromosome 17q24.2-q253 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. (C) 2013 The Authors. Published by Elsevier B.V. All rights reserved.

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