Human galactosemia due to deficiency of galactose-1- phosphate uridyltransferase (GALT) is an enigmatic disease. A galactose restricted diet although alleviating neonatal galactose toxicity does not prevent later complications, cognitive impairment, ovarian failure and neurologic ataxia. The inefficacy of diet therapy has mandated a vigorous effort to understand the pathobiochemical basis of the disease in order to develop new therapeutic strategies. The limitations of clinical studies of affected patients prompted the construction of a """"""""knock-out"""""""" mouse where a portion of the GALT gene has been deleted thereby eliminating GALT enzyme activity. These animals, however, do not develop the human phenotype and show no evidence of galactose toxicity even when fed galactose. This suggests that the absence of GALT is necessary but not sufficient to produce disease. It appears obvious that factors other than the GALT gene mutation play an important role. The GALT knock-out mouse provides a valuable in vivo test tube to determine the metabolic explanation why these animals do not develop the human phenotype.
The aim of this proposal is to examine two possibilities: first, that there is insufficient formation of the metabolite, galactitol, which together with galactose-1-phosphate is necessary to produce the human phenotype; and, second, that there is a robust alternate pathway for galactose disposal. These will be studied by: 1) genetic manipulation to construct a transgenic mouse which expresses human aldose reductase and, when bred with the GALT-deficient animal, will form high levels of galactitol as well as galactose- 1-phosphate and a human phenotype; and, 2) vigorous investigation of metabolic pathways employing isotopic galactose and sophisticated analytic techniques. Great insight into understanding the human condition will be gained by discerning why the GALT knock-out mouse does not exhibit the human galactosemic phenotype.
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