Department of Neurology, the Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, China.
Department of Brain Function and Neuroelectrophysiology, the Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, China.
Seizure. 2023 Oct;111:172-177. doi: 10.1016/j.seizure.2023.08.008. Epub 2023 Aug 18.
The APC2 gene, encoding adenomatous polyposis coli protein-2, is involved in cytoskeletal regulation in neurons responding to endogenous extracellular signals and plays an important role in brain development. Previously, the APC2 variants have been reported to be associated with cortical dysplasia and intellectual disability. This study aims to explore the association between APC2 variants and epilepsy.
Whole-exome sequencing (WES) was performed in cases (trios) with epilepsies of unknown causes. The damaging effects of variants were predicted by protein modeling and in silico tools. Previously reported APC2 variants were reviewed to analyze the genotype-phenotype correlations.
Four pairs of compound heterozygous missense variants were identified in four unrelated patients with epilepsy without brain malformation/intellectual disability. All variants presented no or low allele frequencies in the controls. The missense variants were predicted to be damaging by silico tools, and affect hydrogen bonding with surrounding amino acids or decreased protein stability. Patients with variants that resulted in significant changes in protein stability exhibited more severe and intractable epilepsy, whereas patients with variants that had minor effect on protein stability exhibited relatively mild phenotypes. The previously reported APC2 variants in patients with complex cortical dysplasia with other brain malformations-10 (CDCBM10; MIM: 618677) were all truncating variants; in contrast, the variants identified in epilepsy in this study were all missense variants, suggesting a potential genotype-phenotype correlation.
This study suggests that APC2 is potentially associated with epilepsy without brain malformation/intellectual disability. The genotype-phenotype correlation helps to understand the underlying mechanisms of phenotypic heterogeneity.
APC2 基因编码腺瘤性结肠息肉蛋白-2，参与神经元对内源性细胞外信号的细胞骨架调节，在大脑发育中发挥重要作用。先前的研究报道 APC2 变体与皮质发育不良和智力障碍有关。本研究旨在探讨 APC2 变体与癫痫之间的关联。
对病因不明的癫痫患者（三联体）进行全外显子组测序（WES）。通过蛋白质建模和计算工具预测变体的破坏性影响。回顾先前报道的 APC2 变体，分析基因型-表型相关性。
在 4 名无脑畸形/智力障碍的癫痫患者中发现了 4 对复合杂合错义变体。所有变体在对照组中的等位基因频率均较低或无。计算工具预测错义变体具有破坏性，影响与周围氨基酸的氢键或降低蛋白质稳定性。导致蛋白质稳定性发生显著变化的变体的患者表现出更严重和难治性癫痫，而对蛋白质稳定性影响较小的变体的患者表现出相对较轻的表型。先前在伴有其他脑畸形的复杂皮质发育不良-10 患者（CDCBM10；MIM：618677）中报道的 APC2 变体均为截断变体；相比之下，本研究中在癫痫患者中鉴定出的变体均为错义变体，提示存在潜在的基因型-表型相关性。
本研究提示 APC2 可能与无脑畸形/智力障碍的癫痫有关。基因型-表型相关性有助于理解表型异质性的潜在机制。
