arthritis. Direct injection of vectors expressing 
i8-galactosidase has been shown to lead to selective 
expression of the recombinant gene product in syno- 
vial cells. The hypothesis is that in joints, as in the 
thyroid, injection of DNA into a fluid compartment 
that is normally remodeled by pinocytosis will lead 
to gene expression in cells reabsorbing the fluid. 
Studies are under way to extend these observations 
to generate animal models of arthritis as well as 
methods for treating various forms of arthritis with 
gene medicines. 
The project described above was supported by a 
grant from the National Institutes of Health. 
Dr. Ledley is also Associate Professor of Cell Bi- 
ology and Pediatrics at Baylor College of Medicine 
and a member of the Section on Gastroenterology 
and Nutrition at Texas Children 's Hospital. 
Articles 
Crane, A.M., Jansen, R., Andrews, E.R., and Led- 
ley, F.D. 1992. Cloning and expression of a mu- 
tant methylmalonyl coenzyme A mutase with 
altered cobalamin affinity that causes mut~ meth- 
ylmalonic aciduria. / Clin Invest 89:385-391. 
Crane, A.M., Martin, L.S., Valle, D., and Ledley, 
F.D. 1992. Phenotype of disease in three patients 
with identical mutations in methylmalonyl CoA 
mutase. Hum Genet 89:259-264. 
Hinds, M., Deisseroth, K., Mayes, J., Altschuler, E., 
Jansen, R., Ledley, F.D., andZwelling, L.A. 1991. 
Identification of a point mutation in the topoiso- 
merase II gene from a human leukemia cell line 
containing an amsacrine-resistant form of topo- 
isomerase II. Cancer Res 51:4729-4731. 
Ledley, F.D. 1991. Clinical application of geno- 
typic diagnosis for phenylketonuria: theoretical 
considerations. Eur f Pediatr 150:752-756. 
Ledley, F.D. 1992. The application of gene therapy 
to pediatric practice. Int Pediatr 1:1 -X'b. 
Ledley, F.D. 1992. Somatic gene therapy in gastro- 
enterology: approaches and applications. / Pe- 
diatr Gastroenterol Nutr 14:528-551 ■ 
Ledley, F.D., Woo, S.L., Ferry, G.D., Whisennand, 
H.H., Brandt, M.L., Darlington, G.J., Demmler, 
G.J., Finegold, M.J., Pokorny, W.J., Rosenblatt, H., 
Schwartz, P., Moen, R.C., and Anderson, W.F. 
1991 . Hepatocellular transplantation in acute he- 
patic failure and targeting genetic markers to he- 
patic cells. Hum Gene Ther 2:331-358. 
Shapira, S.K., Ledley, F.D., Rosenblatt, D.S., and 
Levy, H.L. 1991 . Ketoacidotic crisis as a presenta- 
tion of "benign" methylmalonic acidemia. / Pe- 
diatr 119:80-84. 
Vaden, S.L., Wood, P.A., Ledley, F.D., Cornwell, 
P.E., Miller, R.T., and Page, R. 1992. Cobalamin 
deficiency associated with methylmalonic acide- 
mia in a cat. / Am Vet Med Assoc 200:1101- 
1113. 
EUKARYOTIC GENE EXPRESSION 
Stephen A. Liebhaber, M.D., Investigator 
Dr. Liebhaber's laboratory is studying the expres- 
sion and function of the human a-globin gene and 
growth hormone gene clusters. These studies ad- 
dress both transcriptional and post-transcriptional 
controls critical to the high-level, tissue-specific, 
and developmentally controlled expression of these 
genes. An additional and overlapping area of investi- 
gation that utilizes these two gene clusters as model 
systems is the study of the relationship of RNA struc- 
ture to its processing and function. 
Structural Determinants of Human a-Globin 
Gene Expression 
Globin genes are expressed exclusively in differ- 
entiating erythroblasts, where levels of globin 
mRNA constitute >90% of total mRNA. In addition 
to this remarkably specific and high-level expres- 
sion, the expression of individual genes within the 
cluster is developmentally controlled so as to maxi- 
mize the fit between their oxygen-binding activities 
and changing ambient oxygen tensions. Studies in 
this laboratory focus specifically on the expression 
of the human a-globin gene cluster that contains an 
embryonic (D globin gene and two coexpressed 
fetal/adult a-globin genes. 
Recent studies of RNA from embryonic erythroid 
tissue have demonstrated that the switch from ^ to 
a-globin gene expression occurs between the sixth 
and eighth week of gestation. To study this switch in 
further detail. Dr. Liebhaber and his colleagues have 
reconstituted the entire human a-globin gene clus- 
ter along with an adjacent chromatin activation do- 
GENETICS 221 
