GFM1 – Mitochondrial Disease

The association between GFM1 and mitochondrial disease is supported by extensive evidence from both case reports and multi‐patient studies. Patients typically present with a spectrum of severe mitochondrial dysfunction, including progressive hepatoencephalomyopathy, encephalopathy, failure to thrive, and lactic acidemia. Multiple independent studies have reported compound heterozygous mutations in GFM1 that correlate with combined oxidative phosphorylation (OXPHOS) deficiencies, thereby reinforcing its critical role in mitochondrial translation (PMID:23430926).

Genetic investigations across diverse families have demonstrated an autosomal recessive inheritance pattern. For instance, several studies describe siblings and unrelated probands carrying two distinct GFM1 variants, where segregation analysis confirmed inheritance from asymptomatic parents. The genetic evidence is underpinned by the identification of both frameshift and missense mutations with consistent phenotypic consequences, providing a molecular basis for the observed mitochondrial dysfunction (PMID:33093908).

A representative variant that exemplifies the mutational spectrum in GFM1 is c.688G>A (p.Gly230Ser). This missense mutation, reported in multiple studies, affects a highly conserved residue across species. Its presence has been confirmed in independent patient cohorts, and its deleterious impact on protein function is supported by in silico predictions and its absence in healthy population databases (PMID:23430926).

Segregation data from familial analyses further substantiate the role of GFM1 in disease causation, with affected relatives in these families exhibiting matching compound heterozygous mutations. Additional case reports demonstrate a robust correlation between the presence of these mutations and the development of multi‐systemic mitochondrial dysfunction, thereby bolstering the genetic evidence (PMID:25852744).

Functional and experimental assessments provide further insight into the pathogenic mechanism. Studies using patient-derived fibroblasts and animal models have confirmed that GFM1 mutations impair mitochondrial protein synthesis, leading to defects in multiple respiratory chain complexes. Structural analyses and biochemical rescue experiments reinforce the concept that the disruption of mitochondrial translation is central to the pathogenesis of this disorder (PMID:21119709; PMID:28216230).

Collectively, the integration of genetic and functional data establishes a strong association between GFM1 variants and mitochondrial disease. This evidence not only informs diagnostic decision‑making in affected infants but also provides a solid foundation for future therapeutic explorations. Key take‑home message: robust genetic and experimental evidence supports the clinical utility of screening GFM1 in patients with early‐onset mitochondrial dysfunction.

References

• JIMD reports • 2012 • Infantile Progressive Hepatoencephalomyopathy with Combined OXPHOS Deficiency due to Mutations in the Mitochondrial Translation Elongation Factor Gene GFM1 PMID:23430926
• Experimental and therapeutic medicine • 2020 • Clinical and molecular findings in a family expressing a novel heterozygous variant of the G elongation factor mitochondrial 1 gene PMID:33093908
• Frontiers in genetics • 2015 • Long-term Survival in a Child with Severe Encephalopathy, Multiple Respiratory Chain Deficiency and GFM1 Mutations PMID:25852744
• Mitochondrion • 2012 • Toward Genotype Phenotype Correlations in GFM1 Mutations PMID:21986555
• Journal of molecular biology • 2005 • Structural Insights into Fusidic Acid Resistance and Sensitivity in EF-G PMID:15843024
• European journal of human genetics : EJHG • 2011 • Mutation in Subdomain G' of Mitochondrial Elongation Factor G1 is Associated with Combined OXPHOS Deficiency in Fibroblasts but Not in Muscle PMID:21119709
• Mitochondrion • 2017 • Activation of a Cryptic Splice Site in the Mitochondrial Elongation Factor GFM1 Causes Combined OXPHOS Deficiency PMID:28216230

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