Neonatal mitochondrial hepatoencephalopathy caused by novel GFM1 mutations

Ravn, Kirstine; Schönewolf‐Greulich, Bitten; Hansen, Rikke Middelhede; Bohr, Anna-Helene; Dunø, Morten; Wibrand, Flemming; Østergaard, Elsebet

doi:10.1016/j.ymgmr.2015.01.004

Cited by 14 publications

(21 citation statements)

References 11 publications

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“…The human homologue of the bacterial EF-G is present in the mitochondria (G elongation factor mitochondrial 1, GFM1), and it plays similar roles in human protein biosynthesis. Human GFM1 gene mutation, can cause neonatal mitochondrial hepatoencephalopathy (19). The homology between the bacterial protein and the human protein at the amino acid levels is 61% by BLASTP search (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Cross—reactivity of antibodies against microbial proteins to human tissues as basis of Crohn’s disease and other autoimmune diseases

Zhang¹,

Minardi²,

Kuenstner³

et al. 2017

Preprint

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Section: Resultsmentioning

confidence: 99%

Cross—reactivity of antibodies against microbial proteins to human tissues as basis of Crohn’s disease and other autoimmune diseases

Zhang¹,

Minardi²,

Kuenstner³

et al. 2017

Preprint

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“…Knockout of Gfm1 in mice results in embryonic lethality underscoring its critical role in mitochondrial translation and embryogenesis (IMPC Release: 10.0, (Koscielny et al, 2014)). Moreover, mutations in GFM1 have been linked to severe and frequently lethal neonatal pathologies presenting as neurological disease with or without liver involvement (Antonicka, Sasarman, Kennaway, & Shoubridge, 2006;Balasubramaniam et al, 2012;Brito et al, 2015;Calvo et al, 2012;Coenen et al, 2004;Galmiche et al, 2012;Kohda et al, 2016;Ravn et al, 2015;Simon et al, 2017;Smits et al, 2011;Valente et al, 2007).…”

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confidence: 99%

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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“…A study by Sajid et al (29) demonstrated that inhibiting TUFM phosphorylation through drug treatment inhibited the protein synthesis and growth of cells. In addition, Ravn et al (30) observed that TUFM and other translation protein deficiencies in patients with clinical mitochondrial protein translation system defects cause lethal effects during the early neonatal period, whereas, in other patients, TUFM causes serious defects and oxidation-respiration chain enzyme dysfunction in the liver and muscle system. The importance of mitochondrial function in maintaining cell activity is clear.…”

Section: Discussionmentioning

confidence: 99%

TUFM‑knockdown inhibits the migration and proliferation of gastrointestinal stromal tumor cells

Weng¹,

Zheng

Shui

et al. 2020

Oncol Lett

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Gastrointestinal stromal tumors (GISTs) are the most common pathologic type of mesenchymal tumor in the digestive tract. Patients with GIST face the risk of metastasis, postoperative recurrence and imatinib mesylate (IM) resistance. Mitochondrial Tu translation elongation factor (TUFM) is highly expressed in GISTs, and is associated with oncogenesis, progression and prognosis. There is evidence that TUFM is involved in tumor invasion and metastasis. However, the effect of TUFM on GIST-T1 cells and the IM-resistant GIST-IR cell line remains unclear. The present study aimed to evaluate the effects of TUFM on the proliferation, migration and apoptosis of GIST cells in vitro. TUFM short hairpin (sh)RNA expression plasmids were transfected into GIST-T1 and GIST-IR cells by electroporation. The expression levels of enhanced green fluorescent protein were observed by fluorescence microscopy to evaluate the electroporation efficiency. The expression levels of TUFM were detected by western blot analysis and reverse transcription-quantitative PCR. Cell proliferation was assessed by counting cells and using a Cell Counting Kit-8 assay. Cell migration was analyzed using wound healing and Transwell migration assays. Cell cycle distribution and late apoptosis were assessed by flow cytometry. TUFM shRNA expression plasmids were successfully transfected into the GIST cell line by electroporation. The transfection efficiency was >75%, and the TUFM gene silencing efficiency was 73.2±1.4%. TUFM-knockdown decreased the proliferation and migration capacity of GIST-T1 and GIST-IR cells. The proportion of cells in the pre-G1 stage was increased without change in the proportions of cells in the G 1 , S and G 2 /M stages after TUFM silencing in GIST-T1 and GIST-IR cells. TUFM may be related to GIST infiltration and metastatic recurrence, suggesting that TUFM may be an effective target for preventing the progression and metastasis of GISTs.

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Neonatal mitochondrial hepatoencephalopathy caused by novel GFM1 mutations

Cited by 14 publications

References 11 publications

Cross—reactivity of antibodies against microbial proteins to human tissues as basis of Crohn’s disease and other autoimmune diseases

Cross—reactivity of antibodies against microbial proteins to human tissues as basis of Crohn’s disease and other autoimmune diseases

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

TUFM‑knockdown inhibits the migration and proliferation of gastrointestinal stromal tumor cells

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