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A promoter-associated polymorphic repeat modulates PAX-6 expression in human brain.

O Okladnova·Y V Syagailo·M Tranitz·G Stöber·P Riederer·R Mössner·K P Lesch
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Abstract

The PAX-6 gene plays a critical role in neurodevelopment and brain plasticity. While transcription of human PAX-6 is regulated by alternate usage of two distinct promoters termed A and B, expression in adult human 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 approximately 1 kb upstream of the transcription initiation site associated with promoter B. PCR-based systematic screening for length variations in a caucasian population showed a skewed distribution of multiple alleles containing between 24 and 36 repeat units. In 217 unrelated individuals, the frequency of alleles in the range between 25 and 29 repeats was 90%, with the 26 repeat allele alone accounting for 50%; the heterozygosity rate was 65%. Variants of this PAX-6 gene-linked polymorphic region (PAX-6LPR) had different transcriptional efficiencies when fused to a luciferase reporter gene and transfected into Cos-7 cells. Promoter activity of variants with >/=29 repeats was 4- to 9-fold higher than that of the 26 repeat allele. The influence of the PAX-6LPR on PAX-6 expression was confirmed in postmortem cerebellum from individuals with different genotypes. mRNA levels were 2-fold higher in genotypes with long alleles compared to those with short alleles. Allelic variation in PAX-6 expression may be a determinant of interindividual differences in brain plasticity and function.

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AllelesBrainDNA-Binding ProteinsDinucleotide RepeatsEye ProteinsGene Expression RegulationGenes, ReporterHomeodomain ProteinsHumansNerve Tissue ProteinsPAX6 Transcription FactorPaired Box Transcription FactorsPolymerase Chain ReactionPolymorphism, GeneticPromoter Regions, GeneticRNA, MessengerRepetitive Sequences, Nucleic AcidRepressor ProteinsWhite PeopleJournal ArticleResearch Support, Non-U.S. Gov't

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O Okladnova, Y V Syagailo, M Tranitz, G Stöber, P Riederer, R Mössner, K P Lesch. 1998-07-20. A promoter-associated polymorphic repeat modulates PAX-6 expression in human brain.. https://doi.org/10.1006/bbrc.1998.8972

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