Mutational analysis of the tau gene in progressive supranuclear palsy

Objective: To identify genetic mutations in the coding regions and the splice-donor sites of the tau gene on chromosome 17q in individuals with progressive supranuclear palsy (PSP). Background: Several studies provide evidence for linkage disequilibrium between a PSP disease gene and allelic variants of the tau gene. However, a causative mutation has not been identified. Methods: We designed a study to search for genetic mutations in 15 coding regions of the tau gene including the splice-donor sites in 22 patients with PSP by comparing the mobility shifts on single-strand conformation analysis with those of age-matched controls. Fragments with altered migration were sequenced directly and compared for differences in nucleotide composition. Restriction enzyme digests were used to confirm single base-pair substitutions. Results: Significant differences in mobility shifts were found in exons 1, 4A, and 8 between affected individuals and age-matched controls. All individuals with PSP had a common extended haplotype characterized by a homozygous polymorphism in the 5' splice site untranslated region of exon 1, two missense mutations in exon 4A ((Asp)285(Asn), (Ala)289(Val)), and a nonsense mutation in the 5' splice site of exon 8. Conclusions: This study demonstrates that 22 unrelated progressive supranuclear palsy (PSP) patients have four identical sequence variants within the tau gene that are not present in 24 age-matched controls. Although the functional significance of these results on tau protein expression is unknown, the presence of this "susceptibility" haplotype in individuals may place them at risk for developing PSP.