Toward genotype phenotype correlations in GFM1 mutations

Galmiche, Louise; Serre, Valérie; Beinat, Marine; Zossou, Raïssa; Assouline, Zahra; Lèbre, Anne-Sophie; Chretien, Florence; Shenhav, Ruthie; Zeharia, Avraham; Saada, Ann; Vedrenne, Vanessa; Boddaert, Nathalie; Lonlay, Pascale de; Rio, Marlène; Münnich, Arnold; Rötig, Agnès

doi:10.1016/j.mito.2011.09.007

Cited by 22 publications

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“…Nine patients had liver involvement, which was originally reported as an important diagnostic hallmark of GFM1 ‐linked diseases. However, we only detected two cases of liver involvement in our cohort while Galmiche et al () did not identify GFM1 mutations as a prevalent cause of liver failure in a cohort of 26 patients. Interestingly, cardiomyopathy is underrepresented in patients with GFM1 mutations with only one single case of left ventricular hypertrophy being hitherto reported.…”

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“…Using targeted exome sequencing (see supplemental information) we identified compound heterozygous or homozygous GFM1 variants in all nine patients. Two of the variants, NM_024996.5:c.2011C>T p.(Arg671Cys) in patients 1, 2, 5, 6, 8, and 9 and NM_024996.5: c.1404del p.(Gly469Valfs*84) in patient 2 were previously reported (Brito et al, ; Calvo et al, ; Galmiche et al, ). Ten variants were identified for the first time (Figures a and a and Table S2) and include six, predictably pathogenic, missense mutations affecting evolutionary conserved amino acids NM_024996.5:c.958C>G p.(Pro320Ala); NM_024996.5:c.1922C>A p.(Ala641Glu); NM_024996.5:c.248A>T p.(Asp83Val); NM_024996.5:c.1546T>C p.(Cys516Arg); NM_024996.5:c.1571C>T p.(Ala524Val) and NM_024996.5:c.1822C>T p.(Arg608Trp) in patients 3, 4, 5, 7, and 9; one nonsense mutation, NM_024996.5:c.100C>T p.(Arg34*), in patient 6, leading to a premature stop codon in the mitochondrial targeting sequence of EFG1; one frameshift mutation causing a premature stop codon, NM_024996.5:c.1297_1300del p.(Asp433Lysfs*20) in patient 1; one deletion of four amino acids, NM_024996.5:c.1149_1160del p.(Ile384_Thr387del) in patient 4; and an intragenic duplication in patient 7.…”

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Clinical, neuroimaging and biochemical findings in patients and patient fibroblasts expressing ten novel GFM1 mutations

et al. 2019

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Pathogenic GFM1 variants have been linked to neurological phenotypes with or without liver involvement, but only a few cases have been reported in the literature.Here, we report clinical, biochemical, and neuroimaging findings from nine unrelated children carrying GFM1 variants, 10 of which were not previously reported. All patients presented with neurological involvement-mainly axial hypotonia and dystonia during the neonatal period-with five diagnosed with West syndrome; two children had liver involvement with cytolysis episodes or hepatic failure. While two patients died in infancy, six exhibited a stable clinical course. Brain magnetic resonance imaging showed the involvement of basal ganglia, brainstem, and periventricular white matter. Mutant EFG1 and OXPHOS proteins were decreased in patientʼs fibroblasts consistent with impaired mitochondrial translation. Thus, we expand the genetic spectrum of GFM1linked disease and provide detailed clinical profiles of the patients that will improve the diagnostic success for other patients carrying GFM1 mutations. K E Y W O R D S EFG1, GFM1, mitochondrial diseases, mitochondrial translation, OXPHOS *Metodi D. Metodiev and Benedetta Ruzzenente contributed equally to this study.study did not include brain biopsies, the neurological phenotype that has now emerged as the predominant clinical presentation of GFM1 mutations remains to be explained. Future studies will include more comprehensive biochemical and molecular analyses of patient biopsies as well as animal models expressing GFM1 disease-causing variants to understand their tissue-specific clinical presentations. ACKNOWLEDGMENTSWe would like to thank the families for their participation in this study. This work was supported in part by grants from the French association against myopathies (AFM-Telethon) to M.D.M. (nrs. 19876 and 22529) and to B.R. (nr. 22251); and grant GENOMITANR-15-RAR3-0012-07 to A.R. CONFLICT OF INTERESTSThe authors declare that there are no conflict of interests. ORCID Manuel Schiffhttp://orcid.org/0000-0001-8272-232XMetodi D. Metodiev

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Clinical, neuroimaging and biochemical findings in patients and patient fibroblasts expressing ten novel GFM1 mutations

et al. 2019

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“…A combined CI and CIV deficiency in patient heart and skeletal muscle, but isolated CIV deficiency in fibroblasts, indicates that the MRPL44 defect affects the respiratory chain in a tissue-specific manner. Variable tissue manifestations of respiratory chain deficiency are well documented in mitochondrial translation disorders, such as in the translation factor GFM1,28 29 but tissue-specificity in the case of ribosomal subunits is surprising, and the underlying mechanisms remain to be revealed 30–32…”

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Whole-exome sequencing identifies a mutation in the mitochondrial ribosome protein MRPL44 to underlie mitochondrial infantile cardiomyopathy

et al. 2013

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“…In addition to the TRMU gene, two genes have also been recently associated with early-onset liver disorders by translation defect: GFM1 (elongation factor EFG1) and TUFM (elongation factor EFTu). Nevertheless, the TRMU gene emerged as the best candidate gene, because liver dysfunction was present and predominant in all cases described (Valente et al 2007;Galmiche et al 2012;Zeharia et al 2009). Pathogenic TRMU mutations were found in every patient: c.835G>A (p.Val279Met)/c.248 þ 1G>A (splicing alteration) (P1); c.835G>A/c.649G>A (p.Glu217Lys) (P2); c.697C>T (p.Leu233Phe)/c.697C>T (P3).…”

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Mitochondrial Infantile Liver Disease due to TRMU Gene Mutations: Three New Cases

et al. 2013

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Combined respiratory chain defect is a common feature in mitochondrial liver disease during early infancy. Mitochondrial DNA depletions, induced by mutations of the nuclear genes POLG, DGUOK, and MPV17, are the major causes of these combined deficiencies. More recently, mutations in TRMU gene encoding the mitochondrial tRNA-specific 2-thiouridylase were found in infantile hepatopathy related to mitochondrial translation defect. It is characterized by a combined defect of respiratory chain complexes without mitochondrial DNA depletion.We report here clinical, biochemical, and genetic findings from three unrelated children presenting with hepatopathy associated with hyperlactatemia and respiratory chain defect due to bi-allelic mutations in TRMU gene. Two patients recovered spontaneously in a few months, whereas the other one died of acute liver failure. Spontaneous remission is a rare feature in mitochondrial liver diseases, and early identification of TRMU mutations could impact on clinical management. Our results extend the small number of TRMU mutations reported in mitochondrial liver disorders and allowed accumulating data for genotype-phenotype correlation.

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Toward genotype phenotype correlations in GFM1 mutations

Cited by 22 publications

References 23 publications

Clinical, neuroimaging and biochemical findings in patients and patient fibroblasts expressing ten novel GFM1 mutations

Clinical, neuroimaging and biochemical findings in patients and patient fibroblasts expressing ten novel GFM1 mutations

Whole-exome sequencing identifies a mutation in the mitochondrial ribosome protein MRPL44 to underlie mitochondrial infantile cardiomyopathy

Mitochondrial Infantile Liver Disease due to TRMU Gene Mutations: Three New Cases

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