Methylmalonic acidemia (MMA) is an autosomal recessive disorder, caused by the deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT). It is characterized by metabolic instability, multiorgan pathology, and poor prognosis for long-term survival. Deletion of Mut in mice results in neonathal lethality, thus, to overcome this limitation, we have generated novel transgenic mice that have the Mut knockout background but express the Mut gene under the control of a muscle-specific creatine kinase promoter (Mut-/- Tg INS-Mck-Mut). These animals are viable but display massive elevations of serum metabolites, severe growth retardation, and precisely replicate the hepatorenal mitochondropathy and renal failure seen in patients. Mut-/-;TgINS-MCK-Mut mice are fragile and require a high carbohydrate, high fat diet as well as heating pads to survive, but despite these measures, only attain 40% of the bodyweight of age, sex and diet matched littermates. This transgenic mouse model is a valuable research tool to further understand the pathological mechanism of MMA, which can help in developing accurate diagnostics and more effective targeted treatments.
This transgenic mouse model is a valuable research tool to further understand the pathological mechanism of MMA, which can help in developing accurate diagnostics and more effective targeted treatments.
These mice precisely replicate the most important features of MUT MMA in that they have total hepatic MUT deficiency, growth retardation, kidney disease, high levels of disease related metabolites, and diet sensitivity yet can be rescued with liver directed gene therapy, and thus they represent a unique reagent to test liver directed therapies for MUT MMA.