Mutation in the tRNA-modification enzyme GTPBP3 causes hypertrophic cardiomyopathy with abnormal respiratory chain assembly. M. METODIEV1, Z. ASSOULINE2, M. RIO2, F. FEILLET3, B. MOUSSON de CAMARET4, D. CHRETIEN1, A. MUNNICH1,2, A. RÖTIG1 1) INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 24 Boulevard du Montparnasse, 75015 Paris, France; 2) Departments of Pediatrics and Genetics, Hôpital Necker-Enfants Malades, 149 Rue de Sèvres, 75015 Paris, France; 3) Service de médecine infantile, Hôpital d'enfants de Brabois, CHU de Nancy, Rue du Morvan, 54511 Vandoeuvre-les Nancy, France; 4) des Maladies Héréditaires du Métabolisme, CHU de Lyon, 59 bd Pine, 69677 Bron.

   Hypertrophic cardiomyopathy caused by oxidative phosphorylation deficiency has been hitherto ascribed to either altered respiratory chain assembly or impaired translation of proteins encoded by the mitochondrial genome. Exome sequencing in two sibs, with severe hypertrophic cardiomyopathy and combined respiratory chain defect allowed to identify a homozygous frameshift mutation (c.32_33delinsGTG) in GTPBP3, a protein involved in the post-transcriptional modification of several mitochondrial transfer RNAs. This frameshift mutation caused a premature stop codon, abolished the GTPBP3 protein and resulted in an impairment of fully assembled complex I. An abnormal accumulation of an assembly intermediate of complex I with a mild accumulation of the F1F0 subcomplex of complex V was also observed The defect in respiratory chain assembly could be reversed by overexpression of the two wild-type GTPBP3 isoform cDNAs, namely GTPBP3ins8 and GTPBP3del8 in fibroblasts of the affected child. In yeast, the homolog of human GTPBP3, Mss1p, forms a heterodimeric complex with Mto1p and catalyzes the 5-carboxymethylaminomethylation of the wobble uridine base in three mitochondrial tRNAs, namely tRNAGln, tRNAGlu, and tRNALys. Interestingly, mutations in MTO1 have been also shown to cause severe hypertrophic cardiomyopathy in human. In conclusion, we report here that mutation in either subunit of the GTPBP3-MTO1 complex causes severe hypertrophic cardiomyopathy in human.

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