B6-Mmut*M698K/Mmut KO Mouse

The Mmut gene encodes the mitochondrial enzyme methylmalonyl-CoA mutase (MCM), a protein critical for the metabolism of specific amino acids and fatty acids, cholesterol catabolism, and energy production. This gene is widely expressed, with particularly high levels in the liver and kidney. Mutations in Mmut cause methylmalonic acidemia (MMA), a severe autosomal recessive genetic disorder characterized by the accumulation of methylmalonic acid in blood and urine, which triggers life-threatening metabolic crises, developmental delay, and progressive renal failure. The refractoriness of this condition to conventional dietary and pharmacological management has led some patients to undergo elective liver transplantation (LT) or combined liver-kidney transplantation (LKT) to maintain metabolic stability. While LT or LKT reduces the risk of metabolic decompensation, post-transplant patients still exhibit biochemical abnormalities such as elevated methylmalonic acid levels in blood and cerebrospinal fluid. Patients receiving liver transplantation alone remain at risk of renal insufficiency, basal ganglia damage, and optic neuropathy. Additionally, long-term immunosuppressive therapy post-transplant may induce toxic reactions and increase the risk of malignancy ^[1-2]. Current therapeutic strategies for MMA focus on developing drugs that enhance MCM activity or bypass metabolic blocks, including chaperone therapy to improve protein folding and stability, enzyme replacement therapy, and gene therapy strategies to deliver functional Mmut gene copies ^[3-4].

B6-Mmut*M698K/Mmut KO mice are a MMA disease model generated by crossing Mmut-knockout mice (with exon 3 deleted) with Mmut-mutant mice (carrying the p.M698K mutation in exon 12). Homozygous deletion of the gene results in embryonic lethality, and homozygous mutant mice die within 1 day of birth. The p.M698K (ATG to AAG) mutation carried by B6-Mmut*M698K/Mmut KO mice is equivalent to the p.M700K (ATG to AAG) mutation in the human MMUT gene. This model can be used to study the pathogenic mechanisms and therapeutic approaches for MMA.