MOLECULAR GENETIC STUDIES OF GLYCEROL KINASE DEFICIENCY

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DESCRIPTION: (Adapted from investigator's abstract) Glycerol kinase deficiency (GKD) may be caused by deletion of the entire GK gene as part of a contiguous gene syndrome, complex GKD, or by intragenic mutations in isolated GKD. Isolated GKD is associated with two different clinical presentations: the symptomatic form with episodic altered central nervous system status with or without hypoglycemia; or the benign form with incidental observation of pseudohypertriglyceridemia. Using the patients with contiguous gene deletions we cloned two of the genes responsible for the complex phenotype, one of which was GK. It is now proposed to investigate the pathogenesis of GKD by examining the hypothesis that GK mutations will have specific and identifiable effects on GK protein expression and/or function and structure that will alter the concentration and flux of metabolic intermediates involved in glycerolipid and energy metabolism. To pursue this hypothesis the following Specific Aims are proposed: (1) To investigate the effects of GK mutations on GK expression, function and structure we will identify intragenic mutations, determine their effects on expression and function, elucidate their structural consequences, and correlate structure with function in the GK protein; and (2) To understand the pathogenesis of symptomatic GKD, we will investigate the concentration and flux of metabolic intermediates in a knockout mouse model, conditionally rescue or moderate the phenotype to permit survival for metabolic investigations, and introduce wild type and mutant GK genes into the knockout mice by viral mediated gene transfer to study the resulting clinical and biochemical phenotypes. In addition to clarifying the fundamental biology of GK and the pathogenesis of GKD, these investigations will provide basic insights into the dynamics of glycerolipid metabolism and potential tools for studies of tumorigenesis, ethanol oxidation and peroxisomal proliferation.