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

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 MathisRalph Fingerhut, D. Sean Froese, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Matthias R. Baumgartner

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10 Scopus citations


Isolated 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 this strong metabolic condition. We found that Mut-ko/ki mice show common clinical manifestations of MMAuria, including pronounced failure to thrive, indications of mild neurological and kidney dysfunction, and degenerative morphological changes in the liver, along with less well described symptoms such as cardiovascular and hematological abnormalities. The analyses also reveal so far unknown disease characteristics, including low bone mineral density, anxiety-related behaviour and ovarian atrophy. This first phenotypic screening of a MMAuria mouse model confirms its relevance to human disease, reveals new alterations associated with MUT deficiency, and suggests a series of quantifiable readouts that can be used to evaluate potential treatment strategies.

Original languageEnglish
Article number165622
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number3
StatePublished - 1 Mar 2020


  • Decreased cardiac function
  • Failure to thrive
  • Liver phenotype
  • Methylmalonic aciduria
  • Mouse model
  • Ovarian atrophy


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