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-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.
Highlights
Methylmalonic aciduria (MMAuria) is a rare autosomal recessive inborn error of metabolism caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MMUT or MUT) (OMIM entry *609058) [1]
We previously showed that a switch to a high-protein diet (60%-protein) at approximately day 60 of life triggers a significant increase in metabolite levels in Mut knock-out (Mut-ko)/ki mice [13]
A protein-content dependent effect was observed in detection of methylmalonic acid (MMA) (Figure 1 A) and C3 normalized to C2 (Figure 1 B) detected in dried blood spots, whereby the 51%-protein diet led to the strongest increase in biochemical parameters
Summary
Methylmalonic aciduria (MMAuria) is a rare autosomal recessive inborn error of metabolism caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MMUT or MUT) (OMIM entry *609058) [1]. The MUT enzyme catalyses the reversible isomerization of L-methylmalonyl-CoA into succinyl-CoA, an intermediate in the tricarboxylic acid cycle, by using vitamin B12 (cobalamin, Cbl) in its cofactor form 5’-deoxyadenosylcobalamin (AdoCbl). Deficient activity of MUT results either from defects of the MUT apo-enzyme or from defects of intracellular synthesis of AdoCbl. Apo-enzyme defects are traditionally divided into mut0 and mut- classes on the basis of residual in vitro MUT activity, whereby patients classified as mut- retain some residual activity and are responsive in vitro to Cbl supplementation while mut0 are not [3][4]. Patients are often supplemented with carnitine and Cbl, and in order to reduce the throughput of the MUT pathway, a dietary restriction involving a low-protein intake is usually implemented [5][7][8]
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