DNA and RNA of several unrelated Menkes patients 
strongly supports the hypothesis that mutations in 
this gene lead to the Menkes syndrome. 
Analysis and Inactivation of the Murine 
Factor VIII Gene 
Dr. Gitschier's laboratory has a long-standing in- 
terest in the molecular genetics of hemophilia A. 
This X-linked bleeding disorder results from muta- 
tions in the gene coding for coagulation factor VIII, 
a large and unstable clotting cofactor. 
Recent efforts in this laboratory have been di- 
rected toward making a mouse model for hemo- 
philia for future gene therapy experimentation. Por- 
tions of the murine genomic sequences coding for 
factor VIII have been isolated and mutagenized by 
insertion of a neomycin-resistance gene. These se- 
quences will be used to disrupt the native murine 
gene in embryonic stem cells by homologous recom- 
bination. In theory, a factor Vlll-deficient mouse 
could be derived from the targeted cells. 
In a complementary investigation, the murine 
cDNA has been isolated and sequenced. The pre- 
dicted protein shows almost 90% amino acid iden- 
tity with the human protein in the A and C domains, 
portions of the molecule that are required for activ- 
ity. In contrast, the sequences of the B domains, 
which are dispensable, are only 50% identical. Se- 
quence of the murine cDNA, as well as factor VIII 
cDNAs from other species, should be valuable for 
interpretation of the effects of missense mutations 
on the structure or function of factor VIII. 
The hemophilia research described above was 
supported through a grant from the National Insti- 
tutes of Health. 
Dr. Gitschier is also Associate Professor of Medi- 
cine at the University of California, San Fran- 
cisco. 
Articles 
Faust, C.J., Levinson, B., Gitschier, J., and Her- 
man, G.E. 1992. Extension of the physical map in 
the region of the mouse X chromosome homolo- 
gous to human Xq28 and identification of an 
exception to conserved linkage. Genomics 
13:1289-1295. 
Gitschier, J., Kogan, S., Diamond, C, and Levin- 
son, B. 1991. Genetic basis of hemophilia A. 
Thromb Haemost 66:37-39. 
Gitschier, J., and Wood, W.I. 1992. Sequence of 
the exon-containing regions of the human factor 
VIII gene. Hum Mol Genet 1:199-200. 
Ken wrick, S., Levinson, B., Taylor, S., Shapiro, A., 
and Gitschier, J. 1992. Isolation and sequence of 
two genes associated with a CpG island 5' of the 
factor VIII gene. Hum Mol Genet 1:179-186. 
Levinson, B., Bermingham, J.R., Jr., Metzenberg, 
A., Ken wrick, S., Chapman, V., and Gitschier, J. 
1992. Sequence of the human factor VIII- 
associated gene is conserved in mouse. Genomics 
13:862-865. 
Metzenberg, A.B., and Gitschier, J. 1992. The 
gene encoding the palmitoylated erythrocyte 
membrane protein, p55, originates at the CpG is- 
land 3' to the factor VIII gene. Hum Mol Genet 
1:97-101. 
CHROMOSOME ORGANIZATION AND GENE FUNCTION IN DROSOPHILA 
Steven Henikoff, Ph.D., Investigator 
Position-Effect Variegation 
When chromosome breaks cause rearrangements 
in the germline of Drosophila, position effects are 
sometimes seen on genes close to the resulting 
breakpoints. The most curious of these position ef- 
fects are those in which heterochromatin (the com- 
pacted pericentromeric regions) and euchromatin 
are juxtaposed. Euchromatic genes next to such 
breakpoints often show variegated expression, indi- 
cating inactivation in some cells but not in others. 
This is a long-range phenomenon, often affecting 
the expression of genes that are on the order of a 
megabase from the breakpoint. Although position- 
effect variegation has been studied for several 
decades, a mechanistic understanding has proved 
elusive. 
One of the most fascinating aspects of this phe- 
nomenon is that inactivation is often clonal, as if a 
decision made early in development is stably trans- 
mitted through several cell generations. However, a 
problem in trying to study clonal inactivation is that 
the phenotype is only seen after cell division is com- 
plete. Work in Dr. HenikofFs laboratory has now led 
to the isolation of a mutation that causes position- 
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