ENU mutagenesis identifies mice with mithochondrial branched-chain aminotransferase deficiency resembling human maple syrup urine disease

Jer Yuarn Wu, Hsiao Jung Kao, Sing Chung Li, Robert Stevens, Steven Hillman, David Millington, Yuan Tsong Chen

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Abstract

Tandem mass spectrometry was applied to detect derangements in the pathways of amino acid and fatty acid metabolism in N-ethyl-N-nitrosourea-treated (ENU-treated) mice. We identified mice with marked elevation of blood branched-chain amino acids (BCAAs), ketoaciduria, and clinical features resembling human maple syrup urine disease (MSUD), a severe genetic metabolic disorder caused by the deficiency of branched-chain α-keto acid dehydrogenase (BCKD) complex. However, the BCKD genes and enzyme activity were normal. Sequencing of branched-chain aminotransferase genes (Bcat) showed no mutation in the cytoplasmic isoform (Bcat-1) but revealed a homozygous splice site mutation in the mitochondrial isoform (Bcat-2). The mutation caused a deletion of exon 2, a marked decrease in Bcat-2 mRNA, and a deficiency in both BCAT-2 protein and its enzyme activity. Affected mice responded to a BCAA-restricted diet with amelioration of the clinical symptoms and normalization of the amino acid pattern. We conclude that BCAT-2 deficiency in the mouse can cause a disease that mimics human MSUD. These mice provide an important animal model for study of BCAA metabolism and its toxicity. Metabolomics-guided screening, coupled with ENU mutagenesis, is a powerful approach in uncovering novel enzyme deficiencies and recognizing important pathways of genetic metabolic disorders.

Original languageEnglish
Pages (from-to)434-440
Number of pages7
JournalJournal of Clinical Investigation
Volume113
Issue number3
DOIs
Publication statusPublished - Feb 2004
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

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