Vela-Amieva Marcela, Delgado-Maldonado Timoteo, Ortega-Valdez Enrique, Rivera Gildardo, López-Velázquez Gabriel, Fernández-Lainez Cynthia
Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Ciudad de México 04530, Mexico.
Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Reynosa 88710, Mexico.
Int J Mol Sci. 2025 Mar 22;26(7):2887. doi: 10.3390/ijms26072887.
Methylmalonic acidemia (MMA) is a genetic condition associated with intellectual disability and a high mortality rate. It is caused by pathogenic variants in the 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 Å in the Wt to 3386 Å, and the dimer formation involved a different set of amino acids. The NM_000255.4:c.322C>T or p.(Arg108Cys) 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.
甲基丙二酸血症（MMA）是一种与智力残疾和高死亡率相关的遗传性疾病。它由编码甲基丙二酰辅酶A变位酶（MUT）的基因突变引起。在墨西哥人群中，最常发现的变异是NM_000255.4:c.322C>T或p.(Arg108Cys)，但其结构致病效应鲜有研究。为了描述p.(Arg108Cys)纯合患者的临床表现并预测其结构致病效应，我们对6例墨西哥MMA p.(Arg108Cys)纯合患者的病历进行了分析。通过分子动力学模拟（MDS）和对接分析了该变异导致的MUT结构变化，并与野生型（Wt）酶进行了比较。患者呈现的主要临床症状为喂养困难、嗜睡和神经发育迟缓，以早发型表型为主，死亡率为83%。我们发现MUT结构有显著变化，特别是在催化结构域，有空腔体积增加、结合底物通道缩短和异常容纳等情况。此外，二聚化界面面积从Wt的1343 Å增加到3386 Å，且二聚体形成涉及不同的一组氨基酸。NM_000255.4:c.322C>T或p.(Arg108Cys)变异与墨西哥MMA患者的严重预后相关，该酶与二级和三级结构的明显拓扑变化有关，这些变化影响了催化结构域、底物容纳和二聚化界面。需要进一步的体外功能研究来证实这些预测，如在患者成纤维细胞中进行酶活性测量。
