142 bp inserted sequence precisely between exons 
3 and 4 that has homology to Alu. This appears to 
be due to a mutation creating a new splice site 
within an Alu sequence in intron 3. Unexpected al- 
lelic heterogeneity has been shown in the 27 Finn- 
ish pedigrees, where at least three and possibly five 
different mutant alleles are found. By mapping and 
analyzing several polymorphic markers within the 
gene, Dr. Valle and his colleagues have also shown 
that one of the mutations discovered in Finns has 
occurred twice: once in ancestors of two Finnish 
families and again in ancestors of an American pedi- 
gree with no known Finnish ancestry. The func- 
tional consequences of these mutations in both 
mammalian and yeast cells and additional aspects 
of the distribution of the alleles in various popula- 
tions are being investigated. 
C. Analysts of the OAT-hybridizing sequence on the 
X chromosome. In collaboration with Dr. H. Leh- 
rach, Dr. Valle has obtained a series of 22 X-linked 
cosmid clones that contain the X-linked OAT- 
hybridizing sequence. These are to be analyzed to 
produce an overlapping restriction map of the 
clones and to search for possible related functional 
genes in this region. 
D. Models for GA of the choroid and retina. Law- 
rence Brody, a student in Dr. Valle's laboratory, has 
produced a transgenic animal using human OAT 
constructs that exhibit dominant negative expres- 
sion characteristics in cultured cells. The transgenic 
animals will be analyzed to determine if expressing 
these mutant human OAT genes inhibits the activity 
of the endogenous murine OAT. 
In collaboration with investigators at the Univer- 
sity of Pennsylvania School of Veterinary Medicine, 
Dr. Valle and his colleagues have also identified a 
second domestic cat with GA; work is in progress 
to attempt to develop a colony of these cats for ex- 
PUBLICATIONS 
periments related to pathophysiology and treat- 
ment of GA. 
II. Phenylalanine Hydroxylase Mutations in Black 
American Phenylketonuric Patients. 
To address the question of the nature and origin 
of the phenylalanine hydroxylase mutations caus- 
ing phenylketonuria in black Americans, Dr. Valle 
and his associates have determined the restriction 
endonuclease haplotypes for this gene in 16 black 
phenylketonuric patients and compared them with 
a large series of black and Caucasian controls. Four 
new haplotypes have been observed, and a unique 
Msp site has been detected in five phenylalanine 
hydroxylase genes from four black patients. This 
site is a polymorphism in extreme linkage dys- 
equilibrium with a previously undescribed mis- 
sense mutation in exon 7 that appears to be the 
disease-producing mutation. 
III. Molecular Basis of Pseudohypoparathyroidism. 
Pseudohypoparathyroidism (pHP), an autosomal 
dominant disorder in calcium homeostasis, is char- 
acterized by short stature, mild intellectual impair- 
ment, and renal unresponsiveness to parathyroid 
hormone. Dr. Michael Levine obtained biochemical 
and mRNA evidence implicating the G^a subunit of 
the G protein as the site of the primary defect in 
this disorder. Together, Drs. Valle and Levine and 
their colleagues studied an affected mother and son 
and showed that both are heterozygous for an initi- 
ator codon mutation in G^a, thereby confirming the 
hypothesis that mutations at this locus can produce 
the pHP phenotype. 
Dr. Valle is also Professor of Pediatrics and of Mo- 
lecular Biology and Genetics at The Johns Hopkins 
University School of Medicine. 
Books and Chapters of Books 
Beaudet, A.L. , Scriver, C.R., Sly WS., Valle, D. , Cooper, D.N., McKusick, VA., and Schmidke, J. 1989- Genetics 
and biochemistry of variant human phenotypes. In The Metabolic Basis of Inherited Disease (Scriver, C.R., 
Beaudet, A.L. , Sly WS., and Valle, D. , Eds.). New York: McGraw-Hill, pp 3-53. 
Valle, D. , and Mitchell, G.A. 1988. Inborn errors of metabolism. In Clinical Nutrition (Paige, D.M., Ed.). New 
York: Mosby pp 609-627. 
Valle, D., and Simell, O. 1989. The hyperornithinemias. In The Metabolic Basis of Inherited Disease (Scriver, 
C.R., Beaudet, A.L., Sly WS., and Valle, D., Eds.). New York: McGraw-Hill, pp 599-627. 
Continued 
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