Chen Eric, Schmitt Jessica, McIntosh Graeme, Young Barry P, Lian Tianshun, Liu Jie, Chen Kexin K, Liston J Beatrice, MacDonald Lily, Wang Bill, Medina Giro Sonia, Boehme Benjamin, Das Mriga, Indran Seevasant, Chao Jesse T, Rogic Sanja, Pavlidis Paul, Allan Douglas W, Loewen Christopher J R
Department of Cellular and Physiological Sciences, The Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, Canada, V6T 1Z3.
Department of Psychiatry and Michael Smith Labs, The Michael Smith Institute, The University of British Columbia, 301-2185 East Mall, Vancouver, BC, Canada, V6T 1Z4.
Genetics. 2025 Sep 3;231(1). doi: 10.1093/genetics/iyaf121.
Pathogenic variants in MECP2 commonly lead to Rett syndrome, where MECP2's function as a DNA cytosine methylation reader is believed critical. MECP2 variants are also cataloged in individuals with autism spectrum disorder (ASD), including nine missense variants which had no known clinical significance at the start of this study. To assess these nine variants as risk alleles for ASD, we developed MECP2 variant functional assays using budding yeast and Drosophila. We calibrated these assays with known pathogenic and benign variants. Our data predict that four ASD variants are loss of function and five are functional. Protein destabilization offers insight into the altered function of some of these variants. Notably, yeast and Drosophila lack DNA methylation, yet all Rett pathogenic and ASD variants located in the methyl DNA-binding domain that we analyzed proved to be loss of function, suggesting a clinically relevant role for non-methyl DNA-binding by MECP2.
MECP2基因的致病性变异通常会导致雷特综合征，其中MECP2作为DNA胞嘧啶甲基化阅读器的功能被认为至关重要。MECP2变异也在自闭症谱系障碍（ASD）个体中被记录，包括九个错义变异，在本研究开始时这些变异尚无已知的临床意义。为了评估这九个变异作为ASD的风险等位基因，我们利用芽殖酵母和果蝇开发了MECP2变异功能测定方法。我们用已知的致病性和良性变异对这些测定方法进行了校准。我们的数据预测，四个ASD变异是功能丧失型，五个是功能型。蛋白质不稳定为其中一些变异功能改变提供了见解。值得注意的是，酵母和果蝇缺乏DNA甲基化，但我们分析的所有位于甲基DNA结合域的雷特致病性和ASD变异都被证明是功能丧失型，这表明MECP2对非甲基DNA的结合具有临床相关作用。
