Novel Mouse Models of Methylmalonic Aciduria Recapitulate Phenotypic Traits with a Genetic Dosage Effect

J Biol Chem. 2016 Sep 23;291(39):20563-73. doi: 10.1074/jbc.M116.747717. Epub 2016 Aug 12.


Methylmalonic aciduria (MMAuria), caused by deficiency of methylmalonyl-CoA mutase (MUT), usually presents in the newborn period with failure to thrive and metabolic crisis leading to coma or even death. Survivors remain at risk of metabolic decompensations and severe long term complications, notably renal failure and neurological impairment. We generated clinically relevant mouse models of MMAuria using a constitutive Mut knock-in (KI) allele based on the p.Met700Lys patient mutation, used homozygously (KI/KI) or combined with a knockout allele (KO/KI), to study biochemical and clinical MMAuria disease aspects. Transgenic Mut(ki/ki) and Mut(ko/ki) mice survive post-weaning, show failure to thrive, and show increased methylmalonic acid, propionylcarnitine, odd chain fatty acids, and sphingoid bases, a new potential biomarker of MMAuria. Consistent with genetic dosage, Mut(ko/ki) mice have lower Mut activity, are smaller, and show higher metabolite levels than Mut(ki/ki) mice. Further, Mut(ko/ki) mice exhibit manifestations of kidney and brain damage, including increased plasma urea, impaired diuresis, elevated biomarkers, and changes in brain weight. On a high protein diet, mutant mice display disease exacerbation, including elevated blood ammonia, and catastrophic weight loss, which, in Mut(ki/ki) mice, is rescued by hydroxocobalamin treatment. This study expands knowledge of MMAuria, introduces the discovery of new biomarkers, and constitutes the first in vivo proof of principle of cobalamin treatment in mut-type MMAuria.

Keywords: amino acid; ammonia; enzyme mutation; genotype-phenotype correlation; inborn error of metabolism; knock-in mouse model; metabolic disease; methylmalonic aciduria; mitochondrial disease; vitamin B12 metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Metabolism, Inborn Errors* / blood
  • Amino Acid Metabolism, Inborn Errors* / genetics
  • Amino Acid Metabolism, Inborn Errors* / pathology
  • Ammonia / metabolism
  • Animals
  • Biomarkers / blood
  • Brain / metabolism
  • Brain / pathology
  • Carnitine / analogs & derivatives
  • Carnitine / blood
  • Dietary Proteins / adverse effects
  • Dietary Proteins / pharmacology
  • Disease Models, Animal
  • Gene Dosage*
  • Gene Knock-In Techniques
  • Kidney / metabolism
  • Kidney / pathology
  • Methylmalonic Acid / blood
  • Methylmalonyl-CoA Mutase* / genetics
  • Methylmalonyl-CoA Mutase* / metabolism
  • Mice
  • Mice, Knockout
  • Phenotype*
  • Quantitative Trait, Heritable*


  • Biomarkers
  • Dietary Proteins
  • propionylcarnitine
  • Ammonia
  • Methylmalonic Acid
  • Methylmalonyl-CoA Mutase
  • Carnitine

Supplementary concepts

  • Methylmalonic acidemia