Novel mouse model of mut- methylmalonic acidemia (MMA) Mut-/- Tg CBAMutG715V : Mut partial-deficiency

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. A well-characterized human mutation, p.G717V, has been introduced into mice. This mutation has been characterized as a "pure" adenosylcobalamin Km mutation. NHGRI scientist have used site-directed mutagenesis to generate the homologous mouse mutation, p.G715V, and verified the kinetic properties of this mutant enzyme in vitro. They have determined that it possesses a similar defect in adenosylcobalamin binding as the human p.G717V enzyme. Partial deficiency animals are ideally suited to the study of disease mechanisms, pharmacogenomics and late onset disease manifestations of MMA. These mice are unique in that they are viable, can be bred in larger quantities than other mouse models, and are much more robust, yet display modest biochemical changes associated with MMA and can be induced to be very sick by a simple manipulation of dietary change.