A PROMOTER-ASSOCIATED POLYMORPHIC REPEAT MODULATES PAX-6 EXPRESSION IN HUMAN BRAIN

The PAX-6 gene plays a critical role in neurodevelopment and brain pla sticity. While transcription of human PAX-6 is regulated by alternate usage of two distinct promoters termed A and B, expression in adult hu man brain is primarily controlled by promoter B. We now report that a novel polymorphic dinucleotide repeat sequence with the structure (AC) (m)(AG)(n) is located similar to 1 kb upstream of the transcription in itiation site associated with promoter B, PCR-based systematic screeni ng for length variations in a caucasian population showed a skewed dis tribution of multiple alleles containing between 24 and 36 repeat unit s. In 217 unrelated individuals, the frequency of alleles in the range between 25 and 29 repeats was 90%, with the 26 repeat allele alone ac counting for 50%; the heterozygosity rate was 65%. Variants of this PA X-6 gene-linked polymorphic region (PAX-6LPR) had different transcript ional efficiencies when fused to a luciferase reporter gene and transf ected into Cos-7 cells. Promoter activity of variants with greater tha n or equal to 29 repeats was 4- to 9-fold higher than that of the 26 r epeat allele. The influence of the PAX-6LPR on PAX-6 expression was co nfirmed in postmortem cerebellum from individuals with different genot ypes. mRNA levels were 2-fold higher in genotypes with long alleles co mpared to those with short alleles. Allelic variation in PAX-6 express ion may be a determinant of interindividual differences in brain plast icity and function. (C) 1998 Academic Press.