title: A knock-out mouse model for methylmalonic aciduria resulting in neonatal lethality.
abstract: Methylmalonic aciduria is a human autosomal recessive disorder of organic acid metabolism resulting from a functional defect in the activity of the enzyme methylmalonyl-CoA mutase. Based upon the homology of the human mutase locus with the mouse locus, we have chosen to disrupt the mouse mutase locus within the critical CoA binding domain using gene-targeting techniques to create a mouse model of methylmalonic aciduria. The phenotype of homozygous knock-out mice (mut-/-) is one of early neonatal lethality. Mice appear phenotypically normal at birth and are indistinguishable from littermates. By 15 h of age, they develop reduced movement and suckle less. This is followed by the development of abnormal breathing, and all of the mice with a null phenotype die by 24 h of age. Urinary levels of methylmalonic and methylcitric acids are grossly increased. Measurement of acylcarnitines in blood shows elevation of propionylcarnitine with no change in the levels of acetylcarnitine and free carnitine. Incorporation of [14C]propionate in primary fibroblast cultures from mut-/- mice is reduced to approximately 6% of normal level, whereas there is no detectable synthesis of mut mRNA in the liver. This is the first mouse model that recapitulates the key phenotypic features of mut0 methylmalonic aciduria.
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria 3052, Australia.
authors.forename: Heidi
authors.initials: H
authors.lastname: Peters
authors.forename: Mikhail
authors.initials: M
authors.lastname: Nefedov
authors.forename: Joseph
authors.initials: J
authors.lastname: Sarsero
authors.forename: James
authors.initials: J
authors.lastname: Pitt
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Fowler
authors.forename: Sophie
authors.initials: S
authors.lastname: Gazeas
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Kahler
authors.forename: Panayiotis A
authors.initials: PA
authors.lastname: Ioannou
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000235:genetics*; D000592:Amino Acid Metabolism, Inborn Errors; D000818:Animals; D015139:Blotting, Southern; D002331:Carnitine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D002951:Citrates / Q000737:chemistry; D004247:DNA / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005838:Genotype; D006720:Homozygote; D008099:Liver / Q000378:metabolism; D008764:Methylmalonic Acid / Q000378:metabolism; D008765:Methylmalonyl-CoA Mutase / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
chemical_list: D002951:Citrates; D012333:RNA, Messenger; C116917:acylcarnitine; C031605:2-methylcitric acid; D008764:Methylmalonic Acid; D004247:DNA; D019883:Alkyl and Aryl Transferases; C019920:cob(I)alamin adenosyltransferase; D008765:Methylmalonyl-CoA Mutase; D002331:Carnitine