Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
Neurogastroenterol Motil. 2023 Jan;35(1):e14472. doi: 10.1111/nmo.14472. Epub 2022 Oct 20.
Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a rare and serious congenital disorder with poor outcomes, where a heterozygous missense mutation is present in the ACTG2 gene. Here, we aimed to investigate the pathogenesis of ACTG2 in MMIHS.
A cohort with 20 patients with MMIHS was screened. Actg2 heterozygous mutant mice were generated using the CRISPR/Cas9 system. Gastrointestinal (GI) motility, voluntary urination, collagen gel contraction, and G-actin/F-actin analysis were performed.
The R257C variant of ACTG2 most frequently occurred in patients with MMIHS and demonstrated the typical symptoms of MMIHS. Actg2 heterozygous mutant mice had dilated intestines and bladders. The functional assay showed a prolonged total time of GI transit and decreased urine spot area. Collagen gel contraction assay and G-actin/F-actin analysis indicated that mutant mice showed reduced area of contraction of smooth muscle cells (SMCs) and impaired actin polymerization.
CONCLUSIONS & INFERENCES: A mouse model demonstrating MMIHS-like symptoms was generated. The Actg2 heterozygous variant impairs SMCs contraction by interfering with actin polymerization, leading to GI motility disorders.
巨膀胱-小结肠-肠蠕动不良综合征（MMIHS）是一种罕见且严重的先天性疾病，预后不良，其 ACTG2 基因存在杂合错义突变。在此，我们旨在研究 ACTG2 在 MMIHS 中的发病机制。
对 20 例 MMIHS 患者进行了队列筛查。使用 CRISPR/Cas9 系统生成 Actg2 杂合突变小鼠。进行胃肠道（GI）蠕动、自主排尿、胶原凝胶收缩和 G-肌动蛋白/F-肌动蛋白分析。
ACTG2 的 R257C 变异最常发生在 MMIHS 患者中，并表现出 MMIHS 的典型症状。Actg2 杂合突变小鼠的肠道和膀胱扩张。功能测定显示 GI 转运的总时间延长，尿斑面积减少。胶原凝胶收缩测定和 G-肌动蛋白/F-肌动蛋白分析表明，突变小鼠的平滑肌细胞（SMCs）收缩面积减小，肌动蛋白聚合受损。
生成了一种表现出 MMIHS 样症状的小鼠模型。Actg2 杂合变体通过干扰肌动蛋白聚合来破坏 SMCs 的收缩，导致 GI 运动障碍。
