Pinsonneault Julia K, Papp Audrey C, Sadée Wolfgang
Department of Pharmacology, Program in Pharmacogenomics, College of Medicine and Public Health, The Ohio State University, Columbus 43210, USA.
Hum Mol Genet. 2006 Sep 1;15(17):2636-49. doi: 10.1093/hmg/ddl192. Epub 2006 Aug 7.
A pVNTR repeat polymorphism located in the promoter region of the X-linked MAOA gene has been associated with mental disorders. To explore the effect of polymorphisms and epigenetic factors on mRNA expression, we have measured allelic expression imbalance (AEI) in female human brain tissue, employing two frequent marker single nucleotide polymorphisms (SNPs) in exon 8 (T890G) and exon 14 (C1409T) of MAOA. This approach compares one allele against the other in the same subject. AEI ratios ranged from 0.3 to 4 in prefrontal cortex, demonstrating the presence of strong cis-acting factors in mRNA expression. Analysis of CpG methylation in the MAOA promoter region revealed substantial methylation in females but not in males. MAOA methylation ratios for the three- and four-repeat pVNTR alleles of MAOA did not correlate with X-chromosome inactivation ratios, determined at the X-linked androgen receptor locus, suggesting an alternative process of dosage compensation in females. The extent of allelic MAOA methylation was highly variable and correlated with AEI (R2=0.5 and 0.7 at two CpG loci), indicating that CpG methylation regulates gene expression. Genetic factors appeared also to contribute to the AEI ratios. Genotyping of 13 MAOA polymorphisms in female subjects showed strong association with a haplotype block spanning from the pVNTR to the marker SNP. Therefore, allelic mRNA expression is affected by genetic and epigenetic events, both with the potential to modulate biogenic amine tone in the CNS.
位于X连锁单胺氧化酶A（MAOA）基因启动子区域的一个pVNTR重复多态性与精神障碍有关。为了探究多态性和表观遗传因素对mRNA表达的影响，我们在女性脑组织中测量了等位基因表达失衡（AEI），采用了MAOA基因第8外显子（T890G）和第14外显子（C1409T）中的两个常见标记单核苷酸多态性（SNP）。这种方法在同一受试者中比较一个等位基因与另一个等位基因。前额叶皮质中的AEI比率在0.3至4之间，表明mRNA表达中存在强大的顺式作用因子。MAOA启动子区域的CpG甲基化分析显示，女性存在大量甲基化，而男性则没有。MAOA的三重复和四重复pVNTR等位基因的甲基化比率与在X连锁雄激素受体位点测定的X染色体失活比率不相关，这表明女性存在另一种剂量补偿过程。等位基因MAOA甲基化程度高度可变，且与AEI相关（在两个CpG位点处R2分别为0.5和0.7），表明CpG甲基化调节基因表达。遗传因素似乎也对AEI比率有贡献。对女性受试者的13个MAOA多态性进行基因分型显示，与从pVNTR到标记SNP的单倍型块有很强的关联。因此，等位基因mRNA表达受遗传和表观遗传事件影响，两者都有可能调节中枢神经系统中的生物胺水平。
