Sequencing of the tau Gene in Frontotemporal Dementia with Prominent Aphasia

The focus of this project is to discover if there is a genetic correlation between aphasia and one or more mutations in the tau gene on chromosome 17. The tau protein's role in vivo involves binding to axonal microtubules to stabilize them and to affect polymerization. When tau becomes phosphorylated it binds to itself instead of the microtubules, thus forming tau deposits (tangles) which contribute to nerve cell death. tau pathologies are found in several types of neurodegenerative diseases. These include Alzheimer's Disease (AD), Fronto-temporal dementia (FTD), and Progressive Supranuclear Palsy (PSP). Mutations in tau have been found to cause familial forms of FTD. About 90% of these mutations are found in or around exon 10. With regard to FTD, mutations are also found in exons 9, 12, and 13. These mutations reduce tau's ability to bind to microtubules. Also, alleles of tau have been associated with the risk of PSP.

Aphasia is a language disorder that results from damage to portions of the brain that are responsible for language. In this project, all patients had FTD with pronounced aphasia. Some types of FTD are caused by tau mutations; these subjects may represent a phenotypic variation of FTD. Examining tau is a logical manner to explore this hypothesis.

The tau gene consists of 14 exons. By sequencing the exons and regions of the introns that flank them, and comparing the sequence of the affected individuals to that of a healthy control, the DNA can be screened for mutations or polymorphisms.

DNA was extracted from blood of aphasia-diagnosed patients. PCR was used to amplify the DNA with primer pairs corresponding to intronic sequences flanking exons 2, 10, and 13. After amplification and purification, the samples were sequenced. Subsequent analysis revealed no mutations in these three exons. Two known polymorphisms were found. One is in the intron following exon 13; 34 nucleotides 3' of the exon a T is changed to a C. The other is in the intron following exon 2; 18 nucleotides 3' of the exon a C is changed to a T. The allele frequency (T) for this polymorphism in this very small sample (0.3) is similar to that of a large genotyped sample of a previous study.

These results indicate that dementia with aphasia is unlikely to be associated with tau mutations because no mutations were found in or around exon 10 (the location of most FTD-related mutations). However, the remaining exons still need to be examined for mutations. In the risk haplotype for PSP, 9 out of 10 cases have no polymorphisms; because polymorphisms were found, it is extremely improbable that dementia with aphasia is assosicated with a risk haplotype similar to PSP.