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

TY - JOUR

T1 - Novel Mouse Models of Methylmalonic Aciduria Recapitulate Phenotypic Traits with a Genetic Dosage Effect

AU - Forny, Patrick

AU - Schumann, Anke

AU - Mustedanagic, Merima

AU - Mathis, Deborah

AU - Wulf, Marie-Angela

AU - Naegele, Nadine

AU - Langhans, Claus-Dieter

AU - Zhakupova, Assem

AU - Heeren, Joerg

AU - Scheja, Ludger

AU - Fingerhut, Ralph

AU - Peters, Heidi L

AU - Hornemann, Thorsten

AU - Thony, Beat

AU - Koelker, Stefan

AU - Burda, Patricie

AU - Froese, D Sean

AU - Devuyst, Olivier

AU - Baumgartner, Matthias R

N1 - Copyright © 2016, The American Society for Biochemistry and Molecular Biology.

PY - 2016/9/23

Y1 - 2016/9/23

N2 - 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 KO 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, 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, 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.

AB - 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 KO 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, 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, 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.

U2 - 10.1074/jbc.M116.747717

DO - 10.1074/jbc.M116.747717

M3 - SCORING: Journal article

C2 - 27519416

VL - 291

SP - 20563

EP - 20573

JO - J BIOL CHEM

JF - J BIOL CHEM

SN - 0021-9258

IS - 39

ER -