Clinical, neuroimaging and biochemical findings in patients and patient fibroblasts expressing ten novel
            <i>GFM1</i>
            mutations

Barcia, Giulia; Rio, Marlène; Assouline, Zahra; Zangarelli, Coralie; Guéguen, Naïg; Dumas, Valerie D; Marcorelles, Pascale; Schiff, Manuel; Slama, Abdelhamid; Barth, Magalie; Hully, Marie; Lonlay, Pascale de; Münnich, Arnold; Desguerre, I.; Bonnefont, Jean‐Paul; Steffann, Julie; Procaccio, Vincent; Boddaert, Nathalie; Rötig, Agnès; Metodiev, Metodi D.; Ruzzenente, Benedetta

doi:10.1002/humu.23937

Cited by 12 publications

(47 citation statements)

References 16 publications

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“…The present study demonstrated that the levels of NDUFA13 were decreased in the liver; however, they were unchanged in the kidney. This observation was not surprising given that the nuclear-encoded OXPHOS complex I protein NDUFA13 is unstable during complex I assembly and is compromised in mitochondrial translation deficiencies (12), possibly in a tissue-specific manner. Consistent with previous observations (11), the expression level of the OXPHOS complex II protein SDHB was not attenuated in the present study, due to the exclusive nuclear genetic origin of the complex.…”

Section: Discussionmentioning

confidence: 97%

“…The association between GFM1 gene defects and the recessively inherited mitochondrial disorder of oxidative phosphorylation was first reported 15 years ago (3). Over the past decade, the number of families identified to have mutations in this gene is only 25 (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). These patients demonstrated diverse phenotypes; however, the most prevalent clinical feature was liver disease, lactic acidosis, encephalopathy, feeding problems and failure to thrive (11).…”

Section: Discussionmentioning

confidence: 99%

“…In 2004, an association was identified between the mutation of the GFM1 gene and the occurrence of early hepatic encephalopathy, a fatal mitochondrial disease, in two siblings with poor prognosis (3). At present, the total number of GFM1 mutations reported in families is 25 (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

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Clinical and molecular findings in a family expressing a novel heterozygous variant of the G elongation factor mitochondrial 1 gene

Wang

2020

Exp Ther Med

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The identified mutations in the G elongation factor mitochondrial 1 (GFM1) gene have been associated with heterogeneous clinical features of an early-onset mitochondrial disease in only 25 families. The present study reports the case of two siblings with a novel GFM1 variant and their clinical and laboratory presentations, which included progressive hepatic encephalopathy, failure to thrive and persistent lactic acidemia. Both histological changes and diminished expression of the GFM1 protein were observed in the liver and kidney tissues of the index patient. Whole-exome and Sanger sequencing technologies were used to diagnose the index patient with defective GFM1 using amniocentesis at 32 weeks' gestation. Heterozygous mutations in the GFM1 gene were identified in both siblings: A novel mutation, C1576T in exon 13 inherited from their asymptomatic mother, resulting in a premature stop codon at amino acid position 526 and the previously reported G688A mutation on the boundary between exon 5 and intron 5-6, inherited from their asymptomatic father. In conclusion, the present study reports two siblings carrying a novel GFM1 variant with a rare fatal mitochondrial disease.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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Clinical and molecular findings in a family expressing a novel heterozygous variant of the G elongation factor mitochondrial 1 gene

Wang

2020

Exp Ther Med

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“…Meanwhile, metabolic workup generally showed elevated lactic acid, as did the case in this study. Some cases also showed elevated (Barcia et al, 2020;Calvo et al, 2012;Ravn et al, 2015;Simon et al, 2017;Smits et al, 2011).…”

Section: F I G U R Ementioning

confidence: 98%

“…The younger brother had a genetic examination for amniotic fluid before delivery, and he was healthy. Black symbol represents the affected son and daughter by the GFM1 mutations; the arrow represents to the proband; and oblique stripe symbol represents patient with folate deficiency In a study concerning nine unrelated patients carrying GFM1 variants (Barcia et al, 2020), eight patients have compound heterozygous GFM1 mutations. The novel composition of two heterozygous mutations of GFM1 gene found in our study was c.679G > A and c.1765-2_1765-1delAG deletion.…”

Section: F I G U R Ementioning

confidence: 99%

A novel composition of two heterozygous GFM1 mutations in a Chinese child with epilepsy and mental retardation

You

Qiu

et al. 2020

Brain and Behavior

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Mitochondria are the energy factories of eukaryotic cells, which contain thousands of proteins that maintain their specific functions. These proteins are encoded by mitochondrial DNA and the nuclear genome. Pathogenic mutations in these mitochondrial genes can cause multiple serious diseases (Scheffer et al., 2017; Thompson et al., 2020). Mitochondrial DNA encodes its own mRNA, rRNA, and tRNA, to synthesize some of the proteins it needs. Proteins encoded by mitochondrial DNA are involved in the composition of oxidative phosphorylation system complexes, so any gene mutation that affects the replication, transcription, and translation of mitochondrial DNA may cause oxidative phosphorylation deficiency (de Laat, Rodenburg, & Smeitink, 2014). Mitochondrial translation is crucial for maintaining

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Whole exome sequencing identifies a novel compound heterozygous GFM1 variant underlying developmental delay, dystonia, polymicrogyria, and severe intellectual disability in a Pakhtun family

Khan

Khan²,

Khan

et al. 2022

American J of Med Genetics Pt A

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Mitochondrial protein synthesis requires three elongation factors including EF-Tu (TUFM; OMIM 602389), EF-Ts (TSFM; OMIM 604723), and EF-G1 (GFM1; OMIM 606639). Pathogenic variants in any of these three members result in defective mitochondrial translation which can impart an oxidative phosphorylation (OXPHOS) deficiency. In this study, we investigated a consanguineous Pakhtun Pakistani family. There were four affected siblings at the time of this study and one affected girl had died in infancy. The index patient had severe intellectual disability, global developmental delay, dystonia, no speech development, feeding difficulties, and nystagmus. MRI brain presented thinning of corpus callosum and polymicrogyria. Whole exome sequencing revealed a novel compound heterozygous variant in GFM1 located on chromosome 3q25.32. Sanger sequencing confirmed recessive segregation of the maternal (NM_001308164.1:c.409G > A; p.Val137Met) and paternal (NM_001308164.1:c.1880G > A; p.Arg627Gln) variants in all the four affected siblings. These variants are classified as "likely-pathogenic" according to the recommendation of ACMG/AMP guideline. GFM1 alterations mostly lead to severe phenotypes and the patients may die in early neonatal life; however, four of the affected siblings had survived till the ages of 10-17 years, without developing any life-threatening conditions. Mostly, in cousin marriages, the pathogenic variants are identical-by-descent, and affected siblings born to such parents are homozygous. Three homozygous variants were shortlisted in the analysis of the WES data, but Sanger sequencing did not confirm their segregation with the disease phenotype. This is the first report from Pakistan expanding pathogenicity of GFM1 gene.

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

Cited by 12 publications

References 16 publications

Clinical and molecular findings in a family expressing a novel heterozygous variant of the G elongation factor mitochondrial 1 gene

Clinical and molecular findings in a family expressing a novel heterozygous variant of the G elongation factor mitochondrial 1 gene

A novel composition of two heterozygous GFM1 mutations in a Chinese child with epilepsy and mental retardation

Whole exome sequencing identifies a novel compound heterozygous GFM1 variant underlying developmental delay, dystonia, polymicrogyria, and severe intellectual disability in a Pakhtun family

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