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

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

Author information

1
From the Division of Metabolism, the Children's Research Center, the radiz-Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, 8006 Zurich, Switzerland, the Zurich Center for Integrative Human Physiology.
2
From the Division of Metabolism, the Children's Research Center, the radiz-Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, 8006 Zurich, Switzerland, the Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland.
3
From the Division of Metabolism.
4
the Division of Clinical Chemistry and Biochemistry, and.
5
Institute of Neuropathology and.
6
the Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland.
7
the Division of Child Neurology and Inherited Metabolic Diseases, University Children's Hospital, 69120 Heidelberg, Germany.
8
Institute of Clinical Chemistry, University Hospital Zurich, 8006 Zurich, Switzerland.
9
the Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany, and.
10
the Children's Research Center, the Swiss Newborn Screening Laboratory, University Children's Hospital Zurich, 8032 Zurich, Switzerland.
11
the Murdoch Children's Research Institute, Metabolic Research, Parkville, Victoria 3052, Australia.
12
the radiz-Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, 8006 Zurich, Switzerland, Institute of Clinical Chemistry, University Hospital Zurich, 8006 Zurich, Switzerland.
13
From the Division of Metabolism, the Children's Research Center.
14
From the Division of Metabolism, the Children's Research Center, the radiz-Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, 8006 Zurich, Switzerland.
15
the radiz-Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, 8006 Zurich, Switzerland, the Zurich Center for Integrative Human Physiology, the Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland.
16
From the Division of Metabolism, the Children's Research Center, the radiz-Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, 8006 Zurich, Switzerland, the Zurich Center for Integrative Human Physiology, matthias.baumgartner@kispi.uzh.ch.

Abstract

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

PMID:
27519416
PMCID:
PMC5034050
[Available on 2017-09-23]
DOI:
10.1074/jbc.M116.747717
[Indexed for MEDLINE]
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