13 November 2001. In a preliminary but tantalizing finding, Chris Conrad and
coworkers reported today that they have found a novel, small gene in an
intron of the tau gene, and that this new gene has a single-nucleotide
polymorphism that occurs in high frequency among AD patients. If replicated
in larger studies, this SNP might turn out to be a new risk factor for
late-onset Alzheimer's disease.
Conrad, now working with Peter Davies at Albert Einstein College of Medicine
in New York, had the idea that a second gene might reside within the tau
sequence when he was an undergraduate student in the lab of the late Tsunao
Saito. He pursued the idea on and off, and has now cloned a small gene of
128 amino acids that lies between exons nine and ten of the tau gene, 2,500
base pairs upstream of axon 9.
Called Saitohin, the gene has no clear homolog. It appears to be expressed
alongside tau, occurring predominantly in fetal brain, testes, and placenta,
and adult neurons and possibly some glia.
Sequencing the gene from different people, Conrad expected great sequence
variability because introns are not conserved. Yet Saitohin turned out to be
highly conserved, having only one single base difference inside its coding
region, which changes the 7th amino acid from glutamine to arginine (Q7R).
Conrad et al. then sequenced the gene in 130 people, including postmortem
brain samples of known AD patients. In this tiny sample, QQ was most
frequent; 13 percent of normals but 30 percent of AD had QR, and of eight
people who had RR, seven had Alzheimer's and one had an unusual type of
This small study raises the question whether Saitohin could be a risk factor
for AD, much like ApoE, said Davies, but he hastened to add that the finding must
first be confirmed in much larger samples of at least one thousand cases.
The scientists do not know what function this gene could have, but Davies
points to a similar example of this clever use of DNA space. Ensconced in
the choline acetyltransferase gene, whose protein catalyzes the synthesis of
acetylcholine, also lies a smaller gene. Called vesicular acetylcholine
transporter, this gene helps package the neurotransmitter into synaptic
vesicles. Likewise, Davies speculates, Saitohin might turn out to have a
function related to tau.-Gabrielle Strobel.
Conrad C, Vianna C, Freeman M, Davies P. A polymorphic gene nested within an intron of the tau gene: implications for Alzheimer's disease. Proc Natl Acad Sci U S A 2002 May 28;99(11):7751-6. Abstract