Molecular Studies of Human Genetic Disease 
In collaboration with Huda Zoghbi, we are at- 
tempting to clone the gene for dominantly in- 
herited spinocerebellar ataxia, a neurological 
disease that is passed from generation to genera- 
tion. The symptoms usually begin in young adult 
life and result in physical disability, mental dete- 
rioration, and death within about 10 years. Re- 
cent studies have localized the gene to a small 
region of chromosome 6. Large DNA clones 
known as yeast artificial chromosomes have been 
isolated from this region, and the tedious task of 
identifying and cloning the disease gene is 
continuing. 
A major new project is the study of cell adhe- 
sion molecules, which are involved in cell- 
surface and cell-cell adherence, particularly as 
they relate to interactions between white blood 
cells and the walls of blood vessels. The genetic 
disease leukocyte adhesion deficiency involves 
the absence of one of these molecules, desig- 
nated CD 18, on the white blood cells and results 
in fatal susceptibility to infections. Some muta- 
tions causing this disease have been determined. 
The disease is an excellent model for attempts at 
somatic gene therapy, and the gene has been in- 
troduced into retroviral vectors. A major focus of 
this work is to generate mouse models with muta- 
tions in these cell adhesion genes. The mouse 
genes for CD 18, intercellular adhesion mole- 
cule- 1 (ICAM-1), and granule membrane pro- 
tein- 140 (GMP-140) have been isolated and se- 
quenced. For CD 18 and lCAM-1, the mouse gene 
has been disrupted in cultured cells, and the cul- 
tured cells are being injected into mouse em- 
bryos to obtain mutant animals. Mouse mutants 
would be valuable for studying the normal bio- 
logic function of the various cell adhesion mole- 
cules. These molecules are likely to be important 
in processes such as infection, inflammation, and 
atherosclerosis. 
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