It is the overall aim of this research program to understand genetic networks and to integrate the genetics of complex traits with the importance of intermediary metabolism in mammals. Thus, my laboratory has two long-term goals: 1) to identify and characterize all genes involved in human galactose metabolism and 2) to delineate the fundamental importance of galactose metabolism in mammalian development, homeostasis and disease. Galactose is a major component of milk sugar, yet its role in normal development and function is unknown. Galactosemia refers to three inherited disorders of galactose metabolism secondary to deficiency of any one of the enzymes of human galactose metabolism. Deficiency of uridine diphospho-galactose (UDP-gal)4'- epimerase (GALE) can involve in its acute form liver disease, failure to thrive and cataract formation. These symptoms, however, disappear upon the institution of a galactose restricted diet. GALE is expressed ubiquitously and the general form of epimerase-deficiency galactosemia involves all tissues. Peripheral GALE-deficiency is very common and is characterized by erythrocytic enzyme deficiency alone. It is usually not associated with any symptoms. The molecular basis of epimerase- deficiency galactosemia is a present completely unknown. We wish to undertake molecular studies to define the genetic basis of both general and peripheral epimerase-deficiency galactosemia. To this end, we will investigate the following two specific aims: 1) clone and characterize a full-length human cDNA and the gene encoding GALE and 2) characterize the molecular genetic basis of epimerase-deficiency galactosemia. Since galactose metabolism is biochemically well understood it is now ripe for molecular analysis. The cloning and characterization of human GALE will open new avenues for research into the molecular basis of epimerase-deficiency galactosemia, a metabolic liver disease. Our proposed studies will be of great significance in understanding the fundamental importance of human galactose metabolism and its associated diseases.
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