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Heterozygous Actg2 mice mimic the phenotype of megacystis microcolon intestinal hypoperistalsis syndrome. | LitMetric
Background : 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.Methods : 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.Key Results : 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.
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