In-depth phenotyping reveals common and novel disease symptoms in a hemizygous knock-in mouse model (Mut-ko/ki) of mut-type methylmalonic aciduria

Publication date: Available online 23 November 2019Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of DiseaseAuthor(s): Marie Lucienne, Juan Antonio Aguilar-Pimentel, Oana V. Amarie, Lore Becker, Julia Calzada-Wack, Patricia da Silva-Buttkus, Lillian Garrett, Sabine M. Hölter, Philipp Mayer-Kuckuk, Birgit Rathkolb, Jan Rozman, Nadine Spielmann, Irina Treise, Dirk H. Busch, Thomas Klopstock, Carsten Schmidt-Weber, Eckhard Wolf, Wolfgang Wurst, Merima Forny, Déborah MathisAbstractIsolated methylmalonic aciduria (MMAuria) is primarily caused by deficiency of methylmalonyl-CoA mutase (MMUT or MUT). Biochemically, MUT deficiency results in the accumulation of methylmalonic acid (MMA), propionyl-carnitine (C3) and other metabolites. Patients often exhibit lethargy, failure to thrive and metabolic decompensation leading to coma or even death, with kidney and neurological impairment frequently identified in the long-term. Here, we report a hemizygous mouse model which combines a knock-in (ki) missense allele of Mut with a knock-out (ko) allele (Mut-ko/ki mice) that was fed a 51%-protein diet from day 12 of life, constituting a bespoke model of MMAuria. Under this diet, mutant mice developed a pronounced metabolic phenotype characterized by drastically increased blood levels of MMA and C3 compared to their littermate controls (Mut-ki/wt). With this bespoke mouse model, we performed a standardized phenotypic screen to assess the whole-body impairments associated with th...
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research