ArticleBMC medical genetics2006
Production and characterization of murine models of classic and intermediate maple syrup urine disease.
Article in BMC medical genetics, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 53 citations in OpenAlex.
- Simplifying supplementation in MSUD: tolerance and acceptability of liquid valine and isoleucine supplements in maple syrup urine disease.Orphanet journal of rare diseases · 2026Article
- Dysfunctional BCAA degradation triggers neuronal damage through disrupted AMPK-mitochondrial axis due to enhanced PP2Ac interaction.Communications biology · 2025Article
- Branched-chain keto acids promote an immune-suppressive and neurodegenerative microenvironment in leptomeningeal disease.bioRxiv : the preprint server for biology · 2023Article
- Metabolon formation regulates branched-chain amino acid oxidation and homeostasis.Nature metabolism · 2022Article
- Role of branched-chain amino acid metabolism in the pathogenesis of obesity and type 2 diabetes-related metabolic disturbances BCAA metabolism in type 2 diabetes.Nutrition & diabetes · 2022Review
- Neonatal gene therapy achieves sustained disease rescue of maple syrup urine disease in mice.Nature communications · 2022Article
- Exposure to leucine induces oxidative stress in the brain of zebrafish.Metabolic brain disease · 2022Article
- Loss of theDisease models & mechanisms · 2020Article
- Metformin inhibits Branched Chain Amino Acid (BCAA) derived ketoacidosis and promotes metabolic homeostasis in MSUD.Scientific reports · 2016Article
- Branched-chain amino acids in metabolic signalling and insulin resistance.Nature reviews. Endocrinology · 2014Review
- Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders.Human molecular genetics · 2014Review
- Benzothiophene carboxylate derivatives as novel allosteric inhibitors of branched-chain α-ketoacid dehydrogenase kinase.The Journal of biological chemistry · 2014Article
- Precise and in situ genetic humanization of 6 Mb of mouse immunoglobulin genes.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Therapeutic hepatocyte transplant for inherited metabolic disorders: functional considerations, recent outcomes and future prospects.Journal of inherited metabolic disease · 2014Review
- Placental amniotic epithelial cells and their therapeutic potential in liver diseases.Frontiers in medicine · 2014Review
- Quantification of branched-chain keto acids in tissue by ultra fast liquid chromatography-mass spectrometry.Analytical biochemistry · 2013Article
- Placental stem cell correction of murine intermediate maple syrup urine disease.Hepatology (Baltimore, Md.) · 2013Article
- Mutation of zebrafish dihydrolipoamide branched-chain transacylase E2 results in motor dysfunction and models maple syrup urine disease.Disease models & mechanisms · 2012Article
- Advances and challenges in the treatment of branched-chain amino/keto acid metabolic defects.Journal of inherited metabolic disease · 2012Review
- Interrupting the mechanisms of brain injury in a model of maple syrup urine disease encephalopathy.Journal of inherited metabolic disease · 2012Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundMaple Syrup Urine Disease (MSUD) is an inborn error of metabolism caused by a deficiency of branched-chain keto acid dehydrogenase. MSUD has several clinical phenotypes depending on the degree of enzyme deficiency. Current treatments are not satisfactory and require new approaches to combat this disease. A major hurdle in developing new treatments has been the lack of a suitable animal model.
methodsTo create a murine model of classic MSUD, we used gene targeting and embryonic stem cell technologies to create a mouse line that lacked a functional E2 subunit gene of branched-chain keto acid dehydrogenase. To create a murine model of intermediate MSUD, we used transgenic technology to express a human E2 cDNA on the knockout background. Mice of both models were characterized at the molecular, biochemical, and whole animal levels.
resultsBy disrupting the E2 subunit gene of branched-chain keto acid dehydrogenase, we created a gene knockout mouse model of classic MSUD. The homozygous knockout mice lacked branched-chain keto acid dehydrogenase activity, E2 immunoreactivity, and had a 3-fold increase in circulating branched-chain amino acids. These metabolic derangements resulted in neonatal lethality. Transgenic expression of a human E2 cDNA in the liver of the E2 knockout animals produced a model of intermediate MSUD. Branched-chain keto acid dehydrogenase activity was 5-6% of normal and was sufficient to allow survival, but was insufficient to normalize circulating branched-chain amino acids levels, which were intermediate between wildtype and the classic MSUD mouse model.
conclusionThese mice represent important animal models that closely approximate the phenotype of humans with the classic and intermediate forms of MSUD. These animals provide useful models to further characterize the pathogenesis of MSUD, as well as models to test novel therapeutic strategies, such as gene and cellular therapies, to treat this devastating metabolic disease.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.