comes from one or both of the two extragenic 
copies. 
Although the sequence contains a large open 
reading frame, initiated by a methionine, coding ca- 
pacity may be a chance property of CG richness of 
the sequence. To address this issue, Dr. Gitschier 
(in collaboration with Dr. Glenn Hammonds at 
Genentech) has analyzed the sequence for coding 
-- likelihood. Two types of algorithms (Staden- 
McLachlan codon usage and Fickett test code) 
strongly predict that the sequence codes for a pro- 
tein. The same algorithms applied to the scrambled 
sequence showed no protein-coding capacity. One 
unexpected outcome was the illustration of a possi- 
ble frameshift in the coding sequence. Antibodies 
are being prepared to identify and isolate the pro- 
tein and to resolve the frameshift question. 
The intron-22 gene is present in a variety of 
mammals, although the gene in other species ap- 
pears to be present in a single copy. Further studies 
in mice indicate that the murine counterpart is also 
transcribed and that it is not located within the fac- 
tor VIII gene. Analysis of the murine intron-22 gene 
could be invaluable for ascribing a function. 
III. Physical Map of Xq28. 
Of the diseases that map to Xq28, the genes re- 
sponsible for only three — hemophilia A, color 
blindness, and glucose-6-phosphate dehydrogenase 
deficiency— have been isolated. Accurate position- 
ing of loci will be the first step in identifying the 
genes responsible for other Xq28 defects, such as 
adrenoleukodystrophy, Emery-Dreifuss muscular 
PUBLICATIONS 
dystrophy, dyskeratosis congenita, nephrogenic dia- 
betes insipidus, and spastic paraplegia, for which 
the biochemical basis is unknown. A number of 
studies have attempted to order the disease loci ge- 
netically using polymorphic DNA probes from 
Xq28, but the results are inconclusive. 
Available DNA probes and cloned genes have 
been used to generate a large-scale physical map of 
Xq28 by pulsed-field gel electrophoresis. The re- 
sulting map covers 3 Mbp, estimated to be about 
one-half of the entire Xq28 region, and includes all 
probes and genes tested. Genes responsible for he- 
mophilia A, glucose-6-phosphate dehydrogenase 
activity, and color blindness have been linked 
within 1.2 Mbp, and the direction of transcription 
for the former two has been established. A number 
of CpG islands have been identified; these may 
serve as tags for other genes in Xq28. This map will 
also provide the basis for systematically isolating 
new polymorphic DNA sequences needed for accu- 
rate genetic mapping in disease families. 
One important question is the orientation of the 
map relative to the telomere and fragile site. At- 
tempts are being made to incorporate the Xq28 
telomere into an extended physical map. Also on- 
going is a collaboration with Dr. Barbara Trask at 
Lawrence Livermore Laboratory to map the Xq28 
sequences physically relative to the telomere by 
in situ hybridization with fluorescently labeled 
probes. 
Dr. Gitschier is also Assistant Professor of Medi- 
cine (Genetics) at the University of California at San 
Francisco. 
Books and Chapters of Books 
Gitschier, J. 1989. The molecular genetics of hemophilia A. In Coagulation and Bleeding Disorders (Zimmer- 
man, T.S., and Ruggeri, Z.M., Eds.). New York: Dekker, pp 23-46. 
Articles 
Gitschier, J. 1988. Maternal duplication associated with gene deletion in sporadic hemophilia. Am J Hum 
Genet 43:274-279. 
Gitschier, J. , Kogan, S., Levinson, B., and Tuddenham, E.G.D. 1988. Mutations of factor VIII cleavage sites in 
hemophilia A. Blood 72:1022-1028. 
Gitschier, J., Levinson, B., Lehesjoki, A.-E., and de la Chapelle, A. 1989. Mosaicism and sporadic haemophilia: 
implications for carrier determination (letter). Lancet 1:273-274. 
Patterson, M., Gitschier, J. , Bloomfield, J., Bell, M., Dorkins, H., Froster-Iskenius, U., Sommer, S., Sobell, J., 
Schaid, D., Thibodeau, S., and Davies, K.E. 1989. An intronic region within the human factor VIII gene is 
duplicated within Xq28 and is homologous to the polymorphic locus DXS115 (767). Am J Hum Genet 
44:679-685. 
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