Sannino S, Padula M C, Managò F, Schaer M, Schneider M, Armando M, Scariati E, Sloan-Bena F, Mereu M, Pontillo M, Vicari S, Contarini G, Chiabrera C, Pagani M, Gozzi A, Eliez S, Papaleo F
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.
Office Médico-Pédagogique, Department of Psychiatry, University of Geneva, Geneva, Switzerland.
Transl Psychiatry. 2017 May 30;7(5):e1141. doi: 10.1038/tp.2017.109.
The catechol-o-methyltransferase (COMT) genetic variations produce pleiotropic behavioral/neuroanatomical effects. Some of these effects may vary among sexes. However, the developmental trajectories of COMT-by-sex interactions are unclear. Here we found that extreme COMT reduction, in both humans (22q11.2 deletion syndrome COMT Met) and mice (COMT-/-), was associated to cortical thinning only after puberty and only in females. Molecular biomarkers, such as tyrosine hydroxylase, Akt and neuronal/cellular counting, confirmed that COMT-by-sex divergent effects started to appear at the cortical level during puberty. These biochemical differences were absent in infancy. Finally, developmental cognitive assessment in 22q11DS and COMT knockout mice established that COMT-by-sex-dichotomous effects in executive functions were already apparent in adolescence. These findings uncover that genetic variations severely reducing COMT result in detrimental cortical and cognitive development selectively in females after their sexual maturity. This highlights the importance of taking into account the combined effect of genetics, sex and developmental stage.
儿茶酚-O-甲基转移酶（COMT）基因变异会产生多效性的行为/神经解剖学效应。其中一些效应可能因性别而异。然而，COMT与性别的相互作用的发育轨迹尚不清楚。在这里，我们发现，在人类（22q11.2缺失综合征COMT Met）和小鼠（COMT-/-）中，极端的COMT减少仅在青春期后且仅在雌性中与皮质变薄有关。分子生物标志物，如酪氨酸羟化酶、Akt和神经元/细胞计数，证实了COMT与性别的不同效应在青春期开始出现在皮质水平。这些生化差异在婴儿期不存在。最后，对22q11DS和COMT基因敲除小鼠的发育认知评估表明，COMT与性别在执行功能上的二分效应在青春期就已经很明显。这些发现揭示了严重降低COMT的基因变异会在雌性性成熟后选择性地导致有害的皮质和认知发育。这突出了考虑基因、性别和发育阶段综合效应的重要性。
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