MTFMT

MTFMT encodes mitochondrial methionyl-tRNA formyltransferase, an enzyme essential for initiating protein synthesis within mitochondria by modifying Met-tRNA into its formylated form. 

Biallelic mutations in MTFMT disrupt this process, leading to impaired oxidative phosphorylation and clinically significant mitochondrial diseases such as Leigh syndrome and Combined Oxidative Phosphorylation Deficiency 15.

What is MTFMT?

The MTFMT gene provides instructions to make mitochondrial methionyl-tRNA formyltransferase (MTFMT), an enzyme critical in mitochondrial protein production. 

MTFMT modifies methionyl-tRNA (Met-tRNA) by adding a formyl group, creating N-formylmethionyl-tRNA (fMet-tRNA). This chemical change is essential for starting the process of mitochondrial protein synthesis, which occurs inside the mitochondria—the cell's energy factories.

In human mitochondria, a single Met-tRNA must serve both as an initiator and elongator tRNA. MTFMT ensures that a portion of this tRNA is formylated so it can be used to initiate translation. 

This process is critical for assembling proteins that support oxidative phosphorylation (OXPHOS), the primary way cells produce ATP.

When is MTFMT Testing or Research Relevant?

MTFMT testing may be relevant in the following scenarios:

Research on Mitochondrial Disorders and Related Conditions

Mutations in MTFMT are linked to serious mitochondrial diseases, particularly:

Leigh Syndrome

A progressive neurological disorder in children marked by motor and cognitive regression, hypotonia, seizures, and brainstem abnormalities.

Combined Oxidative Phosphorylation Deficiency 15 (COXPD15) and Mitochondrial Complex I Deficiency, Nuclear Type 27 (MC1DN27)

These disorders are caused by mitochondrial translation defects affecting multiple organ systems.

Clinical Testing in Suspected Cases

Genetic testing for MTFMT should be considered in individuals with clinical features suggestive of mitochondrial disease. 

This includes early-onset neurological symptoms such as developmental delay or seizures, as well as brain MRI findings consistent with Leigh syndrome, particularly bilateral lesions in the basal ganglia. 

Testing is also appropriate when there is biochemical evidence of mitochondrial dysfunction, such as elevated lactate levels or deficiencies in mitochondrial complex I or IV activity.

MTFMT Genetic Testing: Test Procedure and Interpretation

Testing for MTFMT is performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for MTFMT genetic testing are considered to be without mutations that can alter the activity of the MTFMT proteins.

What Do Mutations in MTFMT Mean?

MTFMT mutations may have the following implications: 

Impaired Mitochondrial Protein Synthesis and Energy Production

Biallelic MTFMT mutations impair Met-tRNA formylation, leading to reduced fMet-tRNA levels and a failure to initiate mitochondrial translation efficiently. 

This disrupts the synthesis of key mitochondrial proteins and compromises ATP production, particularly in energy-demanding tissues like the brain and muscles.

Clinical Manifestations

Symptoms vary by mutation and patient but may include:

• Developmental delay and regression
• Muscle weakness (hypotonia)
• Movement disorders (e.g., dystonia, ataxia)
• Seizures
• Respiratory distress
• Lactic acidosis
• Autonomic symptoms (e.g., labile blood pressure)
• Cardiac and ophthalmic involvement

What Does the Absence of Specific Studied MTFMT Variants Mean?

The absence of MTFMT variants may have the following clinical significance: 

Considering Other Genetic Causes

A negative MTFMT test result does not rule out mitochondrial disease. Many other genes are involved in mitochondrial translation, tRNA modification, and OXPHOS. Further genetic testing (e.g., exome or mitochondrial panels) may be needed.

Limited Interpretation of Isolated Negative Results

An isolated negative result may have limited diagnostic value without a strong clinical suspicion. Test results should always be interpreted in the context of clinical findings, family history, and biochemical data.

Key Pathogenic MTFMT Variants

Key pathogenic MTFMT variants include: 

• c.626C>T / p.Ser209Leu
  
  • Splice defect leading to exon skipping
  • Most common variant; found in most COXPD15 cases
• c.382C>T / p.Arg128Ter
  
  • Nonsense mutation
  • Causes early stop codon
• c.374C>T / p.Ser125Leu
  
  • Missense mutation
  • Reduces transcript level
• c.994C>T / p.Arg332Ter
  
  • Nonsense mutation
  • Disrupts translation
• c.452C>T / p.Pro151Leu
  
  • Missense mutation
  • Decreases protein stability
• c.146_153del / p.Arg49LeufsTer58
  
  • Frameshift deletion
  • Causes severe loss of function
• c.878G>A / p.Ser293Asn
  
  • Missense mutation
  • Associated with infantile epilepsy
• c.73C>T / p.Gln25Ter
  
  • Nonsense mutation
  • Often seen in compound heterozygosity

Functional and Diagnostic Insights

• Genetic Testing: Best done via next-generation sequencing, MitoExome or whole exome sequencing in suspected cases.
• Biochemical Testing: Reduced respiratory complexes I and IV activity may be seen.
• Functional Studies: Patient fibroblasts often show impaired translation, which can be rescued by transducing wild-type MTFMT.
• Molecular Assays: Northern blotting shows loss of fMet-tRNA and buildup of unformylated Met-tRNA.

Subcellular Localization

• Primary: Mitochondria
• Secondary (lower confidence): Cytosol, nucleoplasm, ER

Molecular Features

• Protein Length: 389 amino acids (~43.8 kDa)
• Domains:
  
  • N-terminal domain binds THF
  • C-terminal domain positions Met-tRNA for formylation
• Catalytic Function: Transfers a formyl group from 10-formyltetrahydrofolate to Met-tRNA (EC 2.1.2.9)

Clinical Takeaways

MTFMT plays a critical role in mitochondrial translation and cellular energy production. Biallelic loss-of-function mutations in this gene are known to cause Leigh syndrome and combined oxidative phosphorylation (OXPHOS) deficiency. 

Early identification of pathogenic variants supports timely genetic counseling, allows for targeted supportive care, and helps guide prognostic discussions. The c.626C>T splice variant is the most common pathogenic mutation and should be prioritized in screening panels. 

Functional studies and rescue experiments have confirmed the pathogenicity of many MTFMT mutations and offer additional insight into potential therapeutic avenues.

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