GalTase

Abstract

The GalTase gene encodes two polypeptide isoforms by differential transcription initiation upstream of two in-frame translation initiation codons. The shorter isoform performs a purely biosynthetic function in the Golgi complex, whereas the longer isoform functions both in the Golgi and on the cell surface. This chapter presents a study in which three knockout (KO) strains were constructed. Most of the KO strain 1 GalTase–/– mice exhibited stunted growth, thin skin, sparse hair, and dehydration, and died within the first few weeks of birth. The adrenal cortices were poorly stratified and spermatogenesis was delayed. KO strain 3 GalTase–/– mice also exhibited enhanced proliferation of epithelial cells of the skin and small intestine, and abnormal differentiation in intestinal villi. GalTase isoform was also expressed on the sperm surface where it functions as a gamete receptor during fertilization by binding to its oligosaccharide ligand on the egg coat glycoprotein, ZP3. Aggregation of the GalTase by the multivalent ZP3 oligosaccharides activates a G protein cascade leading to the acrosome reaction. Sperm from the GalTase-null males bound less ZP3 than wild-type sperm, and were unable to undergo the acrosome reaction in response to either zona pellucida glycoproteins or to antiGalTase antiserum. Controls using KO strain 2 sperm which were devoid of the long GalTase isoform showed that the defect in ZP3 binding and inability to undergo the acrosome reaction were a direct result of GalTase deficiency on the sperm surface and not the secondary result of incomplete galactosylation of sperm surface glycoproteins. The results of this study illustrate that incomplete glycosylation of pituitary hormones leads to the creation of hormone antagonists that downregulate subsequent endocrine function, producing polyglandular endocrine insufficiency.