Drosophila melanogaster Models of Galactosemia

Abstract

The galactosemias are a family of autosomal recessive genetic disorders resulting from impaired function of the Leloir pathway of galactose metabolism. Type I, or classic galactosemia, results from profound deficiency of galactose-1-phosphate uridylyltransferase, the second enzyme in the Leloir pathway. Type II galactosemia results from profound deficiency of galactokinase, the first enzyme in the Leloir pathway. Type III galactosemia results from partial deficiency of UDP galactose 4'-epimerase, the third enzyme in the Leloir pathway. Although at least classic galactosemia has been recognized clinically for more than 100 years, and detectable by newborn screening for more than 50 years, all three galactosemias remain poorly understood. Early detection and dietary restriction of galactose prevent neonatal lethality, but many affected infants grow to experience a broad range of developmental and other disabilities. To date, there is no intervention known that prevents or reverses these long-term complications. Drosophila melanogaster provides a genetically and biochemically facile model for these conditions, enabling studies that address mechanism and open the door for novel approaches to intervention.

Keywords: Galactose; Galactosemia; Metabolic disorder; Motor defect; Newborn screening.

Figure 1

The Leloir Pathway of galactose metabolism (red) and recognized bypass routes (blue). The highly conserved Leloir Pathway is comprised of three enzymes: galactokinase (GALK), galactose-1-phosphate uridylyltransferase (GALT), and UDP galactose 4′-epimerase (GALE). Mutations resulting in deficiency of any of these three enzymes lead to a form of galactosemia.