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

Academic Article


  • 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.
  • Authors

    Published In

  • Human Mutation  Journal
  • Digital Object Identifier (doi)

    Author List

  • Assia Batzir N; Kishor Bhagwat P; Larson A; Coban Akdemir Z; BagÅ‚aj M; Bofferding L; Bosanko KB; Bouassida S; Callewaert B; Cannon A
  • Start Page

  • 641
  • End Page

  • 654
  • Volume

  • 41
  • Issue

  • 3