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

Lucienne, Marie; Aguilar-Pimentel, Juan Antonio; Amarie, Oana V.; Becker, Lore; Calzada-Wack, Julia; Silva-Buttkus, Patricia da; Garrett, Lillian; Holter, Sabine M.; Mayer-Kuckuk, Philipp; Rathkolb, Birgit; Rozman, Jan; Spielmann, Nadine; Treise, Irina; Busch, Dirk H.; Klopstock, Thomas; Schmidt-Weber, Carsten; Wolf, Eckhard; Wurst, Wolfgang; Forny, Merima; Mathis, Deborah; Fingerhut, Ralph; Froese, D. Sean; Gailus-Durner, Valerie; Fuchs, Helmut; Hrabe de Angelis, Martin und Baumgartner, Matthias R. (2020): In-depth phenotyping reveals common and novel disease symptoms in a hemizygous knock-in mouse model (Mut-ko/ki) of mut-type methylmalonic aciduria. In: Biochimica et Biophysica Acta-Molecular Basis of Disease, Bd. 1866, Nr. 3, 165622

Abstract

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-camitine (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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Chemie und Pharmazie > Department Biochemie ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie
• ISSN: 0925-4439
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198