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 dementia.
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
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- 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 14; PubMed.