Simonetti Luciane, Ferreira Lucas G A, Vidi Angela Cristina, de Souza Janaina Sena, Kunii Ilda S, Melaragno Maria Isabel, de Mello Claudia Berlim, Carvalheira Gianna, Dias da Silva Magnus R
Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
Front Genet. 2021 Sep 20;12:724625. doi: 10.3389/fgene.2021.724625. eCollection 2021.
Klinefelter syndrome (KS) displays a broad dysmorphological, endocrinological, and neuropsychological clinical spectrum. We hypothesized that the neurocognitive dysfunction present in KS relies on an imbalance in X-chromosome gene expression. Thus, the X-chromosome inactivation (XCI) pattern and neurocognitive X-linked gene expression were tested and correlated with intelligence quotient (IQ) scores. We evaluated 11 KS patients by (a) IQ assessment, (b) analyzing the XCI patterns using both HUMARA and gene assays, and (c) blood RT-qPCR to investigate seven X-linked genes related to neurocognitive development (, , , , , , and ) and in comparison with 14 (male and female) controls. Considering IQ 80 as the standard minimum reference, we verified that the variability in IQ scores in KS patients seemed to be associated with the XCI pattern. Seven individuals in the KS group presented a random X-inactivation (RXI) and lower average IQ than the four individuals who presented a skewed X-inactivation (SXI) pattern. The evaluation of gene expression showed higher expression in KS patients with RXI than in controls ( = 0.0059). Interestingly, the expression of in KS patients with SXI did not differ from that observed in controls. Therefore, our data suggest for the first time that expression is negatively associated with full-scale IQ under the regulation of the type of XCI pattern. The SXI pattern may regulate expression, thereby dampening the impairment in cognitive performance and playing a role in intelligence variability in individuals with KS, which warrants further mechanistic investigations.
克兰费尔特综合征（KS）呈现出广泛的形态学、内分泌学和神经心理学临床谱系。我们推测KS中存在的神经认知功能障碍依赖于X染色体基因表达的失衡。因此，对X染色体失活（XCI）模式和神经认知X连锁基因表达进行了检测，并与智商（IQ）得分相关联。我们通过以下方式评估了11名KS患者：（a）IQ评估；（b）使用HUMARA和基因检测分析XCI模式；（c）血液逆转录定量聚合酶链反应（RT-qPCR），以研究7个与神经认知发育相关的X连锁基因（、、、、、、和），并与14名（男性和女性）对照进行比较。以IQ 80作为标准最低参考值，我们证实KS患者IQ得分的变异性似乎与XCI模式相关。KS组中有7人呈现随机X失活（RXI），其平均IQ低于呈现偏态X失活（SXI）模式的4人。基因表达评估显示，RXI的KS患者中的表达高于对照组（=0.0059）。有趣的是，SXI的KS患者中的表达与对照组中观察到的表达没有差异。因此，我们的数据首次表明，在XCI模式类型的调节下，表达与全量表IQ呈负相关。SXI模式可能调节表达，从而减轻认知表现的损害，并在KS个体的智力变异性中发挥作用，这值得进一步进行机制研究。
