Saitohin: A polymorphic gene in the tau locus

Abstract

A novel gene, Saitohin (STH), has been discovered in the intron between exons 9 and 10 of the human tau gene. STH is an intronless gene that encodes a 128 amino acid protein with no clear homologs. The tissue expression of STH is similar to tau, a gene which is implicated in many neurodegenerative disorders. A single nucleotide polymorphism that results in an amino acid change (Q7R) has been identified in the Saitohin (STH) gene and was initially found to be over-represented in the homozygous state in late onset Alzheimer's disease (AD) subjects. More extensive studies provide limited support for the R allele association with Alzheimer's disease, but confirm an association of the Q allele with the neurodegenerative diseases, progressive supranuclear palsy and argyrophilic grain disease.;Initial nucleotide and amino acid sequence analyses of the STH gene show it has no clear homology to known genes, proteins, signal sequences or motifs. The molecular evolution of the STH gene was undertaken to identify a consensus sequence of the protein and identify its putative domains as a result of the conservation of amino acids. A homologous sequence was found in the appropriate location of the rat and mouse tau genes, but there is no open reading frame allowing STH expression in these species, suggesting a relatively recent evolution of this gene. In some non-human primates, the STH gene was identified, and this was found to differ from the human at 2 of 128 amino acids. All primates in which the STH gene was identified were homozygous for the R allele of STH, suggesting this is the ancestral allele. This observation was surprising, as the Q allele is more common in human populations, and raised the possibility that natural selection has operated to favor individuals carrying this allele. The STH polymorphism is part of the tau gene haplotype, of which two major variants exist in human populations, the Q being part of the H1 haplotype, and the R part of the H2. More detailed studies confirm the H2 haplotype to be the ancestral tau gene. This situation is reminiscent of the evolution of the ApoE gene, another locus that is potentially important for the risk of development of AD.;The STH amino acid sequence did not appear to have a signal sequence and transfection studies confirmed that GFP-STH is localized to the cytosol. Cotransfection, coimmunoprecipitation and ELISA experiments with Tau and GFP-STH have shown some colocalization in the cell but the two proteins do not immunoprecipitate or bind directly to each other. Cotransfection experiments have also shown that STH does not have an effect on the phosphorylation of tau. (Abstract shortened by UMI.).