Okladnova O, Syagailo Y V, Tranitz M, Stöber G, Riederer P, Mössner R, Lesch K P
Department of Psychiatry, University of Würzburg, Füchsleinstrasse 15, Würzburg, 97080, Germany.
Biochem Biophys Res Commun. 1998 Jul 20;248(2):402-5. doi: 10.1006/bbrc.1998.8972.
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.
PAX - 6基因在神经发育和大脑可塑性中起关键作用。人类PAX - 6的转录受两个不同启动子（称为A和B）的交替使用调控，而成人脑中的表达主要由启动子B控制。我们现在报告，一种结构为(AC)m(AG)n的新型多态二核苷酸重复序列位于与启动子B相关的转录起始位点上游约1 kb处。基于PCR的对白种人群长度变异的系统筛查显示，含有24至36个重复单元的多个等位基因分布不均。在217名无关个体中，25至29个重复之间的等位基因频率为90%，仅26个重复的等位基因就占50%；杂合率为65%。当与荧光素酶报告基因融合并转染到Cos - 7细胞中时，这个与PAX - 6基因相关的多态区域（PAX - 6LPR）的变体具有不同的转录效率。重复数≥29的变体的启动子活性比26个重复的等位基因高4至9倍。PAX - 6LPR对PAX - 6表达的影响在不同基因型个体的死后小脑中得到证实。与短等位基因的基因型相比，长等位基因的基因型中的mRNA水平高2倍。PAX - 6表达中的等位基因变异可能是大脑可塑性和功能个体差异的一个决定因素。
