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GFM1
G elongation factor mitochondrial 1
The GFM1 gene encodes mitochondrial translation elongation factor G1, a protein essential for the synthesis of proteins within the mitochondria, impacting cellular energy production. GFM1 provides the blueprint for mitochondrial translation elongation factor G1, an enzyme located in the mitochondria.
GFM1 is located on the long (q) arm of chromosome 3, at band 3q25.32. Arm ratio per GRCh38 - banding schematic.
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Overview
The GFM1 gene provides instructions for creating mitochondrial translation elongation factor G1, an enzyme found within the mitochondria. Mitochondria are often referred to as the 'powerhouses' of the cell because they are responsible for converting energy from food into a usable form through a process called oxidative phosphorylation. The mitochondrial translation elongation factor G1 enzyme is crucial for the production of proteins from the cell's mitochondrial DNA (mtDNA).
These mtDNA-encoded proteins are essential components of the mitochondrial machinery involved in energy production. Pathogenic variants in GFM1 can therefore disrupt this fundamental cellular process, leading to various health conditions.
What the gene does
The GFM1 gene directs the synthesis of mitochondrial translation elongation factor G1 (mEFG1), an enzyme integral to mitochondrial protein synthesis. While most cellular proteins are encoded by nuclear DNA, a subset of proteins and other molecules originate from mitochondrial DNA (mtDNA). mEFG1 facilitates the translation process, which is the mechanism by which genetic instructions from mtDNA are converted into functional proteins.
During translation, messenger RNA molecules derived from mtDNA (mtRNA) interact with ribosomes, which are cellular structures responsible for assembling proteins. The primary role of mEFG1 is to precisely coordinate the movement of mtRNA molecules in relation to the ribosomes. This coordination ensures the accurate and continuous assembly of amino acids into complete proteins, which are vital for components involved in mitochondrial function, including oxidative phosphorylation.
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Chromosome location
The GFM1 gene is situated on chromosome 3, specifically at position 3q25.32. This genomic location refers to the long (q) arm of chromosome 3, within band 25.32. The gene spans a region of the DNA that provides the complete instructions for building the mitochondrial translation elongation factor G1 protein.
Protein structure
The GFM1 gene encodes a protein consisting of 751 amino acids. A key functional region within this protein is the tr-type G domain, spanning amino acids 44-321. This domain is integral to the protein's role as a translation elongation factor, facilitating its interaction with ribosomes and mtRNA during protein synthesis.
Key variants
Variants within the GFM1 gene can lead to alterations in the mitochondrial translation elongation factor G1 protein, affecting its structure or function. Such changes may impair the protein's ability to facilitate mitochondrial protein synthesis, leading to cellular energy deficiencies. These variants are typically identified through genetic testing.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.114_115del | p.Val40fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 |
c.1424del | p.Arg475fs | Pathogenic/Likely pathogenic | ★★☆☆ | See cases |
c.1483G>T | p.Gly495Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 |
c.1525G>T | p.Glu509Ter | Pathogenic/Likely pathogenic | ★★☆☆ | GFM1-related disorder |
c.1632dup | p.Gly545fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 |
c.303dup | p.Ile102fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 |
c.725T>G | p.Leu242Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 |
c.787C>T | p.Gln263Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 |
c.928_929del | p.Leu310fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 |
c.974del | p.Asn325fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the GFM1 gene are associated with inherited conditions primarily affecting mitochondrial function and energy production. These conditions can present with severe neurological and liver dysfunction, often with significant impact on health. One such condition is Combined Oxidative Phosphorylation Deficiency 1.
No disease links recorded for this gene in our reference set.
UK clinical status
In the UK, the GFM1 gene is recognised on several NHS Genomic Medicine Service national panels for inherited conditions. These include panels for DDG2P, Foetal anomalies (R21), Inherited white matter disorders, Intellectual disability, Likely inborn error of metabolism (R98), Mitochondrial disorders, Possible mitochondrial disorder, nuclear genes (R63), Undiagnosed metabolic disorders, and White matter disorders and cerebral calcification - childhood onset. Its inclusion on these panels indicates its clinical relevance for diagnosing and managing these conditions within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the GFM1 gene?
The GFM1 gene provides instructions for mitochondrial translation elongation factor G1, an enzyme critical for producing proteins from mitochondrial DNA. This process is essential for generating energy within cells.
What happens if there is a pathogenic variant in the GFM1 gene?
Pathogenic variants in the GFM1 gene can disrupt the normal function of mitochondrial translation elongation factor G1, leading to impaired mitochondrial protein synthesis and cellular energy deficiencies. This can result in severe health conditions, such as Combined Oxidative Phosphorylation Deficiency 1.
Is GFM1 involved in any specific conditions?
Yes, pathogenic variants in the GFM1 gene are associated with conditions such as Combined Oxidative Phosphorylation Deficiency 1, which can cause severe neurological and liver dysfunction.
References
- Ravn K, Schönewolf-Greulich B, Hansen RM. Neonatal mitochondrial hepatoencephalopathy caused by novel GFM1 mutations. Molecular genetics and metabolism reports. 2015. PMID: 26937387
- Balasubramaniam S, Choy YS, Talib A. Infantile Progressive Hepatoencephalomyopathy with Combined OXPHOS Deficiency due to Mutations in the Mitochondrial Translation Elongation Factor Gene GFM1. JIMD reports. 2012. PMID: 23430926
- Antonicka H, Sasarman F, Kennaway NG. The molecular basis for tissue specificity of the oxidative phosphorylation deficiencies in patients with mutations in the mitochondrial translation factor EFG1. Human molecular genetics. 2006. PMID: 16632485
- Coenen MJ, Antonicka H, Ugalde C. Mutant mitochondrial elongation factor G1 and combined oxidative phosphorylation deficiency. The New England journal of medicine. 2004. PMID: 15537906