Dr. John T. Macdonald Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, 1501 NW 10th Avenue, BRB-610 (M-860), Miami, FL, 33136, USA.
Hum Genet. 2014 Jun;133(6):737-42. doi: 10.1007/s00439-013-1406-0. Epub 2013 Dec 13.
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.
巨膀胱-小肠细小运动不良综合征（MMIHS）的特征为产前起病的膨胀性膀胱伴功能性肠梗阻，需要广泛的外科干预才能存活。虽然它被认为是一种常染色体隐性疾病，但大多数病例是散发性的。通过对一名 MMIHS 患儿进行全外显子组测序，我们在编码平滑肌γ-2 肌动蛋白（ACTG2）的基因中发现了一个从头突变 p.R178L。随后，我们在另一名 MMIHS 患儿中检测到另一个从头 ACTG2 突变 p.R178C。Actg2 转录本主要在小鼠的膀胱和肠道组织中发现。结构分析和功能实验表明，这两种 ACTG2 突变都干扰了 ACTG2 向细肌丝的正确聚合，导致平滑肌收缩功能受损。总之，我们的研究通过鉴定致病的 ACTG2 突变，为 MMIHS 提出了一种发病机制。
