The overall objectives of this project are to find, characterize and preserve mouse models of human inherited metabolic diseases. The screening program to detect potential mouse models includes histopathology for metabolic storage diseases, quantitative amino acid analysis for amino acid metabolic disorders, and urinary organic acid analysis by gas-chromatography-mass spectrometry for organic acidemias. Suspected cases are characterized clinically, pathologically, genetically, and biochemically to establish the nature of the condition and its relevance to a human disorder. Studies are underway to characterize a mutant mouse with short- chain acy1CoA dehydrogenase deficiency which appears to be a model of the human disorders sudden infant death syndrome and the situation in older children known as Reye syndrome. These mice will be characterized metabolically, enzymologically, molecular genetically, neurologically and ultrastructurally. A myelin deficient mutant mouse is being studied, hypothesized to be a model for the myelin deficient component of human Zellweger syndrome. Studies underway include characterization of plasmalogen synthesis in cells grown from this mutant. Finally, studies have begun to develop a mouse model of choice using antisense RNA techniques to block synthesis of mouse B-glucuronidase in cultured cells and eventually in transgenic mice. This technique could revolutionize animal model development with wide application to any disorder that has the associated cloned DNA sequence available.
