MMUT, encoding methyl-malonyl coenzyme A mutase, is crucial in the metabolism of propionate. It functions in the conversion of methylmalonyl-CoA to succinyl-CoA, a key step in the propionate metabolism pathway and the citric acid cycle anaplerosis. Disturbances in this function can lead to methylmalonic acidemia, an inherited organic acid metabolic disease [1-5, 7].

In patients with mut-type methylmalonic acidemia, different mutations in the MMUT gene are associated with varied responses to vitamin B12 treatment. For instance, mutations like c.1663G>A, c.2080C>T are related to complete responsiveness, while c.1741C>T, c.1630_1631GG>TA show partial responsiveness [1]. The c.1663G>A (p.A555T) mutation is relatively rare but is associated with milder clinical and biochemical phenotypes, later onset, better vitamin B12 responsiveness, and better prognosis in Chinese patients [2]. A novel splice site variant c.2125-2A>G in the MMUT gene was found to cause a mild MMA phenotype due to the production of a reduced amount of full-length transcript [3]. In MMUT-KO cell models, there was a mild mitochondrial impairment, and cells showed reduced viability in glutamine-free medium, suggesting compensation for MMUT loss through increased anaplerosis via glutamine or the secondary propionyl-CoA oxidation pathway [4].

In summary, MMUT is essential for normal propionate metabolism. Studies on gene mutations in patients and MMUT-KO cell models have enhanced our understanding of its role in methylmalonic acidemia. These findings are valuable for uncovering the disease mechanisms and developing potential therapeutic strategies related to MMUT-associated metabolic disorders.

References:

1. Yu, Yue, Shuai, Ruixue, Liang, Lili, Gu, Xuefan, Han, Lianshu. 2021. Different mutations in the MMUT gene are associated with the effect of vitamin B12 in a cohort of 266 Chinese patients with mut-type methylmalonic acidemia: A retrospective study. In Molecular genetics & genomic medicine, 9, e1822. doi:10.1002/mgg3.1822. https://pubmed.ncbi.nlm.nih.gov/34668645/

2. Liang, Lili, Shuai, Ruixue, Yu, Yue, Gu, Xuefan, Han, Lianshu. 2021. A rare mutation c.1663G > A (p.A555T) in the MMUT gene associated with mild clinical and biochemical phenotypes of methylmalonic acidemia in 30 Chinese patients. In Orphanet journal of rare diseases, 16, 22. doi:10.1186/s13023-020-01632-0. https://pubmed.ncbi.nlm.nih.gov/33413471/

3. Zhang, Xinjie, Xu, Xiaowei, Shu, Jianbo, Meng, Yingtao, Cai, Chunquan. 2024. A novel MMUT splicing variant causing mild methylmalonic acidemia phenotype. In Heliyon, 10, e26912. doi:10.1016/j.heliyon.2024.e26912. https://pubmed.ncbi.nlm.nih.gov/38455531/

4. Ramon, Charlotte, Traversi, Florian, Bürer, Céline, Froese, D Sean, Stelling, Jörg. 2022. Cellular and computational models reveal environmental and metabolic interactions in MMUT-type methylmalonic aciduria. In Journal of inherited metabolic disease, 46, 421-435. doi:10.1002/jimd.12575. https://pubmed.ncbi.nlm.nih.gov/36371683/