title: Novel Mouse Models of Methylmalonic Aciduria Recapitulate Phenotypic Traits with a Genetic Dosage Effect.
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.
authors: 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.
authors: Patrick
authors: 0000-0003-1877-2976
authors: P
authors: Forny
authors: 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.
authors: Anke
authors: A
authors: Schumann
authors: From the Division of Metabolism.
authors: Merima
authors: M
authors: Mustedanagic
authors: the Division of Clinical Chemistry and Biochemistry, and.
authors: Déborah
authors: D
authors: Mathis
authors: Institute of Neuropathology and.
authors: Marie-Angela
authors: MA
authors: Wulf
authors: the Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland.
authors: Nadine
authors: N
authors: Nägele
authors: the Division of Child Neurology and Inherited Metabolic Diseases, University Children's Hospital, 69120 Heidelberg, Germany.
authors: Claus-Dieter
authors: CD
authors: Langhans
authors: Institute of Clinical Chemistry, University Hospital Zurich, 8006 Zurich, Switzerland.
authors: Assem
authors: A
authors: Zhakupova
authors: the Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany, and.
authors: Joerg
authors: J
authors: Heeren
authors: the Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany, and.
authors: Ludger
authors: L
authors: Scheja
authors: the Children's Research Center, the Swiss Newborn Screening Laboratory, University Children's Hospital Zurich, 8032 Zurich, Switzerland.
authors: Ralph
authors: R
authors: Fingerhut
authors: the Murdoch Children's Research Institute, Metabolic Research, Parkville, Victoria 3052, Australia.
authors: Heidi L
authors: HL
authors: Peters
authors: 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.
authors: Thorsten
authors: T
authors: Hornemann
authors: From the Division of Metabolism, the Children's Research Center.
authors: Beat
authors: B
authors: Thony
authors: the Division of Child Neurology and Inherited Metabolic Diseases, University Children's Hospital, 69120 Heidelberg, Germany.
authors: Stefan
authors: S
authors: Kölker
authors: From the Division of Metabolism, the Children's Research Center.
authors: Patricie
authors: P
authors: Burda
authors: 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.
authors: D Sean
authors: DS
authors: Froese
authors: 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.
authors: Olivier
authors: O
authors: Devuyst
authors: 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.
authors: Matthias R
authors: MR
authors: Baumgartner
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000097:blood / Q000235:genetics / Q000473:pathology; D000641:Ammonia / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood; D004044:Dietary Proteins / Q000009:adverse effects / Q000494:pharmacology; D004195:Disease Models, Animal; D018628:Gene Dosage; D055879:Gene Knock-In Techniques; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008764:Methylmalonic Acid / Q000097:blood; D008765:Methylmalonyl-CoA Mutase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D019655:Quantitative Trait, Heritable
chemical_list: D015415:Biomarkers; D004044:Dietary Proteins; C003223:propionylcarnitine; D000641:Ammonia; D008764:Methylmalonic Acid; D008765:Methylmalonyl-CoA Mutase; D002331:Carnitine
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