Molecular Genetics of Mammalian 
Glycosyltransferases 
John B. Lowe, M.D. — Assistant Investigator 
Dr. Lowe is also Associate Professor of Pathology at the University of Michigan Medical School. He received 
his bachelor's degree in mathematics from the University of Wyoming and his M.D. degree from the 
University of Utah College of Medicine, Salt Lake City. He was trained in clinical pathology and molecular 
genetics at Washington University School of Medicine, St. Louis. He was later Assistant Professor in the 
Departments of Pathology and Medicine at Washington University and also served as Assistant Medical 
Director of the Barnes Hospital blood bank, St. Louis, before moving to Michigan. 
THE primary long-range goal of our research is 
to understand the functions of oligosaccha- 
rides that are found on the surface of mammalian 
cells and to explain how the cells regulate their 
expression. Oligosaccharide molecules consist 
of many different single-sugar structures linked 
together in complex linear and branching arrays. 
Quantitative and structural changes in such mole- 
cules have been shown to correlate with morpho- 
logic changes that occur during the embryonic 
development of animals and in association with 
neoplastic transformation. These and other ob- 
servations suggest that cell surface oligosaccha- 
rides may function as information bearers in me- 
diating interactions between cells during the 
developmental process. 
Mammalian cells, in constructing these mole- 
cules, use special proteins called glycosyltrans- 
ferase enzymes. With few exceptions, a unique 
glycosyltransferase is responsible for the synthe- 
sis of each linkage between the sugar molecules 
in an oligosaccharide. The enormous number of 
different oligosaccharides dictates that many dif- 
ferent glycosyltransferases will enter the con- 
struction of the complex cell surface carbohy- 
drates on any particular cell or tissue. 
In many instances, changes in cell surface car- 
bohydrate structure observed during differentia- 
tion or in association with malignant transforma- 
tion have been shown to correlate with changes 
in the glycosyltransferase repertoire. The mecha- 
nisms by which cells coordinate and regulate the 
expression of these enzymes, and thus the ex- 
pression of oligosaccharide structures at the cell 
surface, are largely unknown. During the past few 
years, the main focus of our work has been in 
establishing systems that will allow molecular 
analysis of the mammalian genes responsible for 
glycosyltransferase synthesis. 
The human ABO, H, and Lewis blood group an- 
tigens are actually cell surface oligosaccharides. 
The determinant genes encode particular glyco- 
syltransferases that are able to construct the 
"blood group" molecules. These glycosyltrans- 
ferases provide convenient genetic and biochemi- 
cal models for studying how the processes regu- 
late cell surface oligosaccharide expression. The 
blood group antigens are not restricted in their 
expression to blood cells. They are found on a 
number of other tissues in the body, suggesting 
that tissue-specific mechanisms regulate their ex- 
pression. Moreover, their expression changes 
during human embryonic development and is of- 
ten altered in malignancy. 
Our initial efforts focused on developing sys- 
tems to isolate glycosyltransferase genes without 
the benefit of purified enzyme protein. Using 
gene transfer approaches, we have been able to 
isolate several of these genes. They include hu- 
man genes encoding the H blood group a(l ,2)fu- 
cosyltransferase and the Lewis blood group 
q;(1,3/1,4) fucosyltransferase . 
The cloned gene segments in each case repre- 
sent tools for investigating the genetics of these 
enzymes and for studying the function and regula- 
tion of their corresponding cell surface oligosac- 
charides. For example, we have recently used the 
H blood group gene to investigate the molecular 
basis for the Bombay blood group phenotype. In- 
dividuals with this blood group are extraordi- 
narily rare and are cross-match incompatible with 
virtually all other humans, excepting other Bom- 
bay individuals. This incompatibility is due to the 
fact that these persons apparently lack a func- 
tional H blood group locus. As a consequence, 
they are unable to construct A, B, or H blood 
group determinants, and thus maintain high titers 
of antibodies directed against the ABH blood 
group structures found on red cells from virtually 
all other humans. 
The molecular basis for the defect in Bombay 
individuals had not been defined. By analyzing 
the structure of the H gene in Bombay pedigrees, 
we identified point mutations in both alleles of 
the gene in affected individuals. We subse- 
quently demonstrated that these mutations inac- 
tivate the enzyme encoded by the gene and are 
thus responsible for the Bombay phenotype. We 
have also analyzed this gene in para-Bombay indi- 
viduals, whose red cells are deficient in ABH 
structures but whose secretory tissues express es- 
sentially normal levels of these molecules (under 
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