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J. Biol. Chem., Vol. 278, Issue 52, 52909-52913, December 26, 2003

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A Knock-out Mouse Model for Methylmalonic Aciduria Resulting in Neonatal Lethality^*

Heidi Peters, Mikhail Nefedov¶, Joseph Sarsero, James Pitt, Kerry J. Fowler||, Sophie Gazeas, Stephen G. Kahler**, and Panayiotis A. Ioannou||

From the Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria 3052, Australia and the ^||Department of Pediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia

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.

Received for publication, September 23, 2003

^* The work was also partially supported by a grant from the Brock-hoff Foundation. This work was approved by the Royal Children's Hospital Animal Ethics Experimentation Committee (Project Number A459). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a postgraduate scholarship from the National Health & Medical Research Council of Australia.

^¶ Present address: BACPAC Resources, Oakland Children's Hospital Research Institute, Oakland, CA.

^** Present address: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins Hospital, Blalock 1008, Baltimore, MD 21287-4922.

To whom correspondence should be addressed: CAGT Research Group, Murdoch Children's Research Institute, Royal Children's Hospital, Flemington Rd., Parkville, Victoria 3052, Australia. Tel.: 61-3-8341-6232; Fax: 61-3-8341-6212; E-mail: ioannoup{at}cryptic.rch.unimelb.edu.au.

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