A promoter-associated polymorphic repeat modulates PAX-6 expression in human brain
A promoter-associated polymorphic repeat modulates PAX-6 expression in human brain
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DOI：
10.1006/bbrc.1998.8972
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发表时间：
1998-07-20
影响因子：
3.1
通讯作者：
Lesch, KP
中科院分区：
文献类型：
--
作者：
Okladnova, O;Syagailo, YV;Lesch, KP
PAX-6基因在神经发育和大脑可塑性中起着关键作用。人类PAX-6的转录受A和B两个不同启动子交替使用的调控，而在成人脑中的表达主要由启动子B控制。我们现在报道了一个新的多态二核苷酸重复序列，其结构为(AC)(M)(AG)(N)，位于与启动子B相关的转录起始点上游类似于1kb的位置。基于PCR的高加索人群长度变异的系统筛查显示，包含24到36个重复单位的多个等位基因的偏态分布。在217个无关个体中，25~29个重复等位基因的频率为90%，其中26个重复等位基因占50%，杂合率为65%。该PAX-6基因连锁多态区域(PAX-6LPR)的变异体与荧光素酶报告基因融合后，在COS-7细胞中的转录效率不同。具有大于或等于29个重复的变异体的启动子活性是26个重复等位基因的4-9倍。证实了PAX-6LPR对不同基因型人死后小脑中PAX-6表达的影响。长等位基因的基因表达水平是短等位基因的2倍。PAX-6表达的等位基因变异可能是大脑可塑性和功能个体间差异的决定因素。(C)1998年学术出版社。
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 similar to 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 greater than or equal to 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. (C) 1998 Academic Press.