Abstract：
Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is characterized by prenatal-onset distended urinary bladder with functional intestinal obstruction, requiring extensive surgical intervention for survival. While it is believed to be an autosomal recessive disorder, most cases are sporadic. Through whole-exome sequencing in a child with MMIHS, we identified a de novo mutation, p.R178L, in the gene encoding the smooth muscle gamma-2 actin, ACTG2. We subsequently detected another de novo ACTG2 mutation, p.R178C, in an additional child with MMIHS. Actg2 transcripts were primarily found in murine urinary bladder and intestinal tissues. Structural analysis and functional experiments suggested that both ACTG2 mutants interfere with proper polymerization of ACTG2 into thin filaments, leading to impaired contractility of the smooth muscle. In conclusion, our study suggests a pathogenic mechanism for MMIHS by identifying causative ACTG2 mutations.
摘要：
巨结肠-微结肠-肠蠕动综合征（MMIHS）的特征是产前发作的膀胱扩张伴功能性肠梗阻，需要广泛的手术干预才能生存。虽然它被认为是一种常染色体隐性遗传疾病，大多数病例是零星的。通过对MMIHS患儿的全外显子组测序，我们发现了一个从头突变，p.R178L,在编码平滑肌γ-2肌动蛋白的基因中，ACTG2。我们随后检测到另一个从头ACTG2突变，p.R178C,在另一个患有MMIHS的孩子中。Actg2转录物主要在小鼠膀胱和肠组织中发现。结构分析和功能实验表明，两种ACTG2突变体都会干扰ACTG2适当聚合成细丝，导致平滑肌收缩性受损。总之,我们的研究通过鉴定致病性ACTG2突变提示了MMIHS的致病机制.
