# The Arg108Cys Variant of Methylmalonyl-CoA Mutase: Clinical Implications for the Mexican Population Based on Molecular Dynamics and Docking

## TL;DR

This study examines the clinical and structural effects of a common genetic variant in the Mexican population with methylmalonic acidemia, revealing severe outcomes and enzyme structural changes.

## Contribution

The study provides new insights into the structural pathogenic effects of the Arg108Cys variant in the MMUT gene specific to the Mexican population.

## Key findings

- The Arg108Cys variant is associated with severe clinical symptoms and an 83% mortality rate in Mexican MMA patients.
- Molecular dynamics simulations revealed significant structural changes in the MUT enzyme, including altered catalytic domain and dimerization interface.
- The variant impacts substrate accommodation and enzyme stability, suggesting a mechanism for its pathogenicity.

## Abstract

Methylmalonic acidemia (MMA) is a genetic condition associated with intellectual disability and a high mortality rate. It is caused by pathogenic variants in the MMUT gene, which codes methylmalonyl-CoA mutase enzyme (MUT). In the Mexican population, the variant NM_000255.4:c.322C>T or p.(Arg108Cys) is the most frequently found, but its structural pathogenic effect is scarcely studied. To describe the clinical picture of p.(Arg108Cys) homozygous patients and to predict its structural pathogenic effect, we performed an analysis of the medical files from six MMA Mexican p.(Arg108Cys) homozygous patients. The structural changes in MUT caused by this variant were analyzed through molecular dynamics simulations (MDS) and docking and compared with the wild-type (Wt) enzyme. The main clinical symptoms presented by the patients were feeding difficulties, lethargy, and neurodevelopmental delay, with a predominance of early-onset phenotype and a mortality rate of 83%. We found significant structural changes in MUT structure, particularly in the catalytic domain, with increased volume cavity, shortening of the binding substrate tunnel, and aberrant accommodation. Also, the dimerization interface area increased from 1343 Å2 in the Wt to 3386 Å2, and the dimer formation involved a different set of amino acids. The NM_000255.4:c.322C>T or p.(Arg108Cys) MMUT variant is associated with a severe outcome in MMA Mexican patients, and the enzyme was associated with ostentatious topological changes in the secondary and tertiary structure, which impacted the catalytic domain, the accommodation of the substrate, and the dimerization interface. Further ex vivo functional studies are needed to confirm these predictions, such as enzymatic activity measurements in fibroblasts of patients.