amino acids. This deletes several carboxyl-terminal 
residues that are highly conserved in ABC trans- 
porter proteins. Functional analyses of these alleles 
are in progress. 
Dr. Valle is also Professor of Pediatrics with 
joint appointments in Medicine, Molecular Biol- 
ogy and Genetics, Biology, and Ophthalmology at 
the Johns Hopkins University School of Medicine. 
Articles 
Brody, L.C., Mitchell, G.A., Obie, C, Michaud, J., 
Steel, G., Fontaine, G., Robert, M.-F., Sipila, I., 
Kaiser-Kupfer, M., and Valle, D. 1992. Ornithine 
5-aminotransferase mutations in gyrate atrophy: 
allelic heterogeneity and functional conse- 
quences. /fi/o/ Chem 267:3302-3307. 
Dougherty, K.M., Brandriss, M.C., and Valle, D. 
1992. Cloning human pyrroline-5-carboxylate re- 
ductase cDNA by complementation in Saccharo- 
myces cerevisiae. J Biol Chem 267:871-875. 
Gartner, J., Moser, H., and Valle, D. 1992. Muta- 
tions in the 70K peroxisomal membrane protein 
gene in Zellweger syndrome. Nature Genet 
1:16-23. 
Geraghty, M.T., Perlman, E.J., Martin, L.S., Hay- 
flick, S.J., Casella, J.F., Rosenblatt, D.S., and 
Valle, D. 1992. Cobalamin C defect associated 
with hemolytic uremic syndrome. / Pediatr 
120:934-937. 
Hamosh, A., McDonald, J.W., Valle, D., Franco- 
mano, C.A., Niedermeyer, E., and Johnston, M.V. 
1992. Dextromethorphan and high-dose ben- 
zoate therapy for nonketotic hyperglycinemia in 
an \ni2.nt. J Pediatr 121:131-135. 
Hayflick, S., Rowe, S., Kavanaugh-McHugh, A., Ol- 
sen, J.L., and Valle, D. 1992. Acute infantile car- 
diomyopathy as a presenting feature of muco- 
polysaccharidosis W. J Pediatr 120:269-272. 
Kaiser-Kupfer, M.I., Caruso, R.C., and Valle, D. 
1991. Gyrate atrophy of the choroid and retina. 
Long-term reduction of ornithine slows reti- 
nal degeneration. Arch Ophthalmol 109:1539- 
1548. 
Kuo, F.C., Hwu, W.L., Valle, D., and Darnell, J.E., Jr. 
1991. Colocalization in pericentral hepatocytes 
in adult mice and similarity in developmental ex- 
pression pattern of ornithine aminotransferase 
and glutamine synthetase mRNA. Proc Natl Acad 
Sci USA 88:9468-9472. 
Michaud, J., Brody, L.C., Steel, G., Fontaine, G., 
Martin, L.S., Valle, D., and Mitchell, G.A. 1992. 
Strand-separating conformational polymorphism 
analysis: efficacy of detection of point mutations 
in the human ornithine 5-aminotransferase gene. 
Genomics 13:389-394. 
Stanley, C.A., DeLeeuw, S., Coates, P.M., Vianey- 
Liaud, C, Divry, P., Bonnefont, J.-P., Saudubray, 
J.-M., Haymond, M., Trefz, F.K., Breningstall, 
G.N., Wappner, R.S., Byrd, D.J., Sansaricq, C, 
Tein, I., Grover, W., Valle, D., and Treem, W.R. 
1991- Chronic cardiomyopathy and weakness or 
acute coma in children with a defect in carnitine 
uptake. Ann Neurol 30:709-716. 
Traboulsi, E.I., Silva, J.C., Geraghty, M.T., Mau- 
menee, I.H., Valle, D., and Green, W.R. 1992. 
Ocular histopathologic characteristics of cobala- 
min C type vitamin B12 defect with methylma- 
lonic aciduria and homocystinuria. Am J Ophthal- 
mol 113:269-280. 
GENETIC DISEASES OF THE HUMAN X CHROMOSOME 
Stephen T. Warren, Ph.D., Associate Investigator 
Fragile X Syndrome 
Since the discovery of the FMR-1 (fragile X men- 
tal retardation 1) gene by Dr. Warren and his collab- 
orators in early 1 99 1 , his laboratory has continued 
to investigate the multitude of interesting aspects of 
this unique locus. A mutation of this locus, asso- 
ciated with a chromosomal fragile site at Xq27.3, is 
responsible for the fragile X syndrome, the most 
common inherited cause of mental retardation. 
Fragile X syndrome is an X-linked dominant dis- 
order with reduced penetrance in both sexes (80% 
in males and 30% in females). It is unusual in that 
penetrance is variable within families, depending 
on the relationship to nonpenetrant transmitting 
males (NTMs). Male siblings of NTMs have a <9% 
risk of mental retardation, yet grandsons of NTMs 
carry a 40% risk. The risk increases up to normal 
Mendelian ratios (i.e., 50% affected sons) by pas- 
sage through female meioses. 
This phenomenon, termed the Sherman paradox, 
is equivalent to genetic anticipation where increas- 
ing clinical involvement and/or earlier age of onset, 
280 
