De novo ACTG2 mutations cause congenital distended bladder, microcolon, and intestinal hypoperistalsis

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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / metabolism
  • Abnormalities, Multiple / pathology
  • Actins / genetics*
  • Animals
  • Base Sequence
  • Child
  • Child, Preschool
  • Colon / abnormalities*
  • Colon / metabolism
  • Colon / pathology
  • DNA Mutational Analysis
  • Exome
  • Female
  • Genes, Recessive
  • Humans
  • Intestinal Pseudo-Obstruction / genetics*
  • Intestinal Pseudo-Obstruction / metabolism
  • Intestinal Pseudo-Obstruction / pathology
  • Male
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Muscle, Smooth / metabolism
  • Muscle, Smooth / pathology
  • Mutation*
  • Pedigree
  • Urinary Bladder / abnormalities*
  • Urinary Bladder / metabolism
  • Urinary Bladder / pathology


  • ACTG2 protein, human
  • Actins

Supplementary concepts

  • Megacystis microcolon intestinal hypoperistalsis syndrome