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A major goal of our research is to understand the molecular basis for the effects of MSUD on the brain as a means to developing effective therapy.

We have generated a mouse line that has what we call a floxed E1-alpha gene that will allow us to ask very fundamental questions about MSUD and brain pathology in an animal model. The animals that we have generated (floxed E1-alpha) have DNA pieces put into them that are recognized by the enzyme Cre-recombinase. By breeding with what we call a Cre-mouse (a mouse which expresses the Cre-recombinase enzyme), we are able to remove a portion of the E1-alpha gene and produce an animal with a defective E1- alpha gene. Through several breeding cycles, we first produce animals that have the defective gene (deletion) in one chromosome (+/- animal) then breed those to make animals that have the deletion in both chromosomes (-/- animal). This is the knockout or KO (-/-) animal, because this animal does not produce the E1- alpha protein (or produces a defective protein with a large piece missing). Today there are mouse lines that permit us to create a knockout in the entire animal or in specific organs and tissues. Ultimately we want to generate a mouse that does not express E1- alpha only in the brain.

We have generated MSUD E1 knockout animals by breeding mice heterozygous (one chromosome has the deletion and the other one is normal) for the E1-alpha gene deletion in both chromosomes (-/- or KO animal). These animals are classic MSUD and, as found with the E2 total knockout (*KO), the pups die within 1-2 days of birth. We are using these animals to show the localization of the branched-chain alpha-keto complex (BCKDC) in the brains of the mice. The enzyme is located in nerves (neurons) and not in other types of brain cells, but expression is not uniform throughout the brain. Right now we are breeding the neuron-specific Cre mouse to establish the line here, and then we will mate them with our E1 animals (floxed E1). Animal breeding is a time-consuming process. We hope to produce the desired animals in the next couple of months. The phenotype of these animals will show whether altering brain metabolism is sufficient to produce the neurological effects and determine the next course of experiments. Stay tuned for further updates.

We are also collaborating with Dr. Brendan Lee at Baylor on the phenylbutyrate project. Our laboratory will be doing the cell work, measuring leucine metabolism and the effects of phenylbutyrate on MSUD patient lymphoblast cell lines to determine whether we can predict efficacy.

Editor’s Note: Please see Dr. Hutson’s article in the Fall 2007 Newsletter for more information on this project.
Editor’s Note: Please see Dr. Lee’s article on front cover.

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