Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy

Hum Mutat. 2020 Mar;41(3):641-654. doi: 10.1002/humu.23960. Epub 2019 Dec 19.


Visceral myopathy with abnormal intestinal and bladder peristalsis includes a clinical spectrum with megacystis-microcolon intestinal hypoperistalsis syndrome and chronic intestinal pseudo-obstruction. The vast majority of cases are caused by dominant variants in ACTG2; however, the overall genetic architecture of visceral myopathy has not been well-characterized. We ascertained 53 families, with visceral myopathy based on megacystis, functional bladder/gastrointestinal obstruction, or microcolon. A combination of targeted ACTG2 sequencing and exome sequencing was used. We report a molecular diagnostic rate of 64% (34/53), of which 97% (33/34) is attributed to ACTG2. Strikingly, missense mutations in five conserved arginine residues involving CpG dinucleotides accounted for 49% (26/53) of disease in the cohort. As a group, the ACTG2-negative cases had a more favorable clinical outcome and more restricted disease. Within the ACTG2-positive group, poor outcomes (characterized by total parenteral nutrition dependence, death, or transplantation) were invariably due to one of the arginine missense alleles. Analysis of specific residues suggests a severity spectrum of p.Arg178>p.Arg257>p.Arg40 along with other less-frequently reported sites p.Arg63 and p.Arg211. These results provide genotype-phenotype correlation for ACTG2-related disease and demonstrate the importance of arginine missense changes in visceral myopathy.

Keywords: ACTG2; dysmotility; megacystis-microcolon intestinal hypoperistalsis; smooth muscle; visceral myopathy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Abnormalities, Multiple / diagnosis
  • Abnormalities, Multiple / genetics
  • Actins / genetics*
  • Adult
  • Amino Acid Substitution*
  • Arginine*
  • Colon / abnormalities
  • DNA Mutational Analysis
  • Exome Sequencing
  • Female
  • Genetic Association Studies*
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Intestinal Pseudo-Obstruction / diagnosis*
  • Intestinal Pseudo-Obstruction / genetics*
  • Male
  • Molecular Diagnostic Techniques
  • Mutation*
  • Phenotype
  • Urinary Bladder / abnormalities
  • Young Adult


  • ACTG2 protein, human
  • Actins
  • Arginine

Supplementary concepts

  • Megacystis microcolon intestinal hypoperistalsis syndrome