Modeling of MFN2 Protein Mutations’ Effects May Predict CMT Type 2A’s Severity

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Molecular simulations of the effects of specific mutations in the structure of mitofusin 2 (MFN2) — the key protein altered in Charcot-Marie-Tooth disease type 2A (CMT2A) — may predict the disease’s severity, a recent study shows.

The study, “Molecular modelling of mitofusin 2 for a prediction for Charcot-Marie-Tooth 2A clinical severity,” was published in the journal Scientific Reports.

CMT2A is caused by mutations in the MFN2 gene, which contains the instructions to produce MFN2, a protein involved in the fusion of mitochondria (the cell’s power plants), an essential process for healthy cellular function.

So far, more than 100 MFN2 mutations have been reported, and most are located in a region that will give rise to a critical domain of the MFN2 protein, the GTPase domain.

These domain-specific mutations are associated with a range of symptoms, from classical peripheral symptoms — muscle weakness and atrophy, and decreased sensation in the feet, lower legs, hands, or forearms — to symptoms related to damage of the central nervous system (brain and spinal cord), including hearing loss and vision deficits.

Also, significant differences in these symptoms have been associated with distinct substitutions of amino acids (the building blocks of proteins) in the MFN2 protein, caused by mutations.

While it is important to establish conclusive associations between mutations and disease severity in these patients, the disease’s complexity has hindered such achievement.

Researchers at Poland’s Mossakowski Medical Research Centre and University of Warsaw  have evaluated whether changes in MFN2 structure caused by MFN2 mutations in the GTPase domain could predict CMT2A severity.

Among the 68 mutations in the GTPase domain reported in the literature, they analyzed only the 26 mutations associated with amino acid substitutions.

The team evaluated the effects of each mutation on the MFN2 protein structure, and predicted the functional consequences and resulting disease severity, using a molecular modeling approach.

The results showed that these mutations had an impact on the various stages of the mitochondria fusion process.

Next, the researchers compared the predicted disease severity associated with specific structural changes caused by the position of the mutation and the properties of the substitute amino acid with the real disease severity of the 26 CMT2A patients carrying the mutations.

Because CMT2A patients’ clinical data were reported by different neurologists using various examination methods, the team developed its own CMT2A scale, which took into account symptoms associated with peripheral, central nervous system, and mitochondrial damage.

The results obtained through molecular modeling showed 73% compatibility with the patients’ clinical data, suggesting that this approach can be used to “predict the [damaging] effect of a mutation in [the GTPase domain of] the MFN2 gene and to anticipate the patient’s prospective clinical outcome,” the researchers stated.

They also found that their approach showed a better predictive value than commonly used tools to assess the clinical effects of a mutation (45% compatibility).

The team believes that this type of analysis also adds knowledge to the mechanism of protein function and that its CMT2A scale could be useful for patients with mutations in the GTPase domain.

“Our analysis revealed that molecular modeling of mitofusin 2 mutations is a powerful tool, which predicts associated pathogenic impacts and that these correlate with clinical outcomes. This approach may aid an early diagnosis and prediction of symptoms’ severity in CMT2A patients,” the researchers said.

Nevertheless, additional, larger studies are required to confirm the predictive value of this approach in MFN2 mutations.