An extended 5 '-tau susceptibility haplotype in progressive supranuclear palsy

Objective: To confirm the association of an extended 5'-tau haplotype on ch romosome 17q with the disease phenotype in clinically ascertained individua ls with sporadic progressive supranuclear palsy (PSP). Background: PSP is a neurodegenerative disease with parkinsonian signs accompanied by vertical supranuclear palsy and tau, pathologic features. Previously, we documented the complete segregation of an extended 5'-tau haplotype consisting of four single nucleotide polymorphisms (SNP) with the disease phenotype in sporad ic PSP. This study was conducted in an independent cohort to confirm these results and to improve the statistical power of the data. Design and Method s: Direct sequencing and restriction enzyme digests were used to analyze fo ur SNP in tau Exons 1, 4A, and 8. These contiguous SNP were used to reconst ruct an extended 5'-tau haplotype in 52 affected and 54 age-matched control individuals. Results: The four SNP formed two homozygous 5'-tau haplotypes (HapA and HapC) or a heterozygous genotype. Fifty-one (98%) patients with PSP had HapA; one (2%) with a later onset was heterozygous; and none had Ha pC. These PSP haplotype frequencies were different (p < 0.00001) from those of the age-matched control group, in which 18 (33%) people had HapA; 26 (4 8%) were heterozygous; and 10 (19%) had HapC. The extended 5'-tau haplotype , HapA, had a high sensitivity (98%) and a moderate specificity (67%) as a marker for PSP. Conclusions: A 5'-tau susceptibility haplotype may be a sen sitive marker for sporadic PSP and a genetic defect in, or closely linked t o, tau may contribute to the cause of PSP.