Abstract：
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. Actg2R257C 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. Actg2R257C 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.
A mouse model demonstrating MMIHS-like symptoms was generated. The Actg2R257C heterozygous variant impairs SMCs contraction by interfering with actin polymerization, leading to GI motility disorders.
A cohort with 20 patients with MMIHS was screened. Actg2R257C 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. Actg2R257C 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.
A mouse model demonstrating MMIHS-like symptoms was generated. The Actg2R257C heterozygous variant impairs SMCs contraction by interfering with actin polymerization, leading to GI motility disorders.
摘要：
背景：Megacystis微结肠肠蠕动综合征（MMIHS）是一种罕见且严重的先天性疾病，预后较差，其中ACTG2基因中存在杂合错义突变。这里,我们旨在探讨ACTG2在MMIHS中的发病机制。
方法：筛选了20名MMIHS患者的队列。使用CRISPR/Cas9系统产生Actg2R257C杂合突变小鼠。胃肠(GI)运动,自愿排尿,胶原蛋白凝胶收缩，并进行G-肌动蛋白/F-肌动蛋白分析。
结果：ACTG2的R257C变体最常见于MMIHS患者，并表现出MMIHS的典型症状。Actg2R257C杂合突变小鼠的肠和膀胱扩张。功能测定显示胃肠道运输的总时间延长，尿斑面积减少。胶原蛋白凝胶收缩测定和G-肌动蛋白/F-肌动蛋白分析表明，突变小鼠显示出平滑肌细胞（SMC）收缩面积减少和肌动蛋白聚合受损。
结论：产生了表现出MMIHS样症状的小鼠模型。Actg2R257C杂合变体通过干扰肌动蛋白聚合来损害SMC的收缩，导致胃肠道运动障碍。
方法：筛选了20名MMIHS患者的队列。使用CRISPR/Cas9系统产生Actg2R257C杂合突变小鼠。胃肠(GI)运动,自愿排尿,胶原蛋白凝胶收缩，并进行G-肌动蛋白/F-肌动蛋白分析。
结果：ACTG2的R257C变体最常见于MMIHS患者，并表现出MMIHS的典型症状。Actg2R257C杂合突变小鼠的肠和膀胱扩张。功能测定显示胃肠道运输的总时间延长，尿斑面积减少。胶原蛋白凝胶收缩测定和G-肌动蛋白/F-肌动蛋白分析表明，突变小鼠显示出平滑肌细胞（SMC）收缩面积减少和肌动蛋白聚合受损。
结论：产生了表现出MMIHS样症状的小鼠模型。Actg2R257C杂合变体通过干扰肌动蛋白聚合来损害SMC的收缩，导致胃肠道运动障碍。
