Heterozygous De Novo and Inherited Mutations in the Smooth Muscle Actin (ACTG2) Gene Underlie Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome

Abstract

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare disorder of enteric smooth muscle function affecting the intestine and bladder. Patients with this severe phenotype are dependent on total parenteral nutrition and urinary catheterization. The cause of this syndrome has remained a mystery since Berdon's initial description in 1976. No genes have been clearly linked to MMIHS. We used whole-exome sequencing for gene discovery followed by targeted Sanger sequencing in a cohort of patients with MMIHS and intestinal pseudo-obstruction. We identified heterozygous ACTG2 missense variants in 15 unrelated subjects, ten being apparent de novo mutations. Ten unique variants were detected, of which six affected CpG dinucleotides and resulted in missense mutations at arginine residues, perhaps related to biased usage of CpG containing codons within actin genes. We also found some of the same heterozygous mutations that we observed as apparent de novo mutations in MMIHS segregating in families with intestinal pseudo-obstruction, suggesting that ACTG2 is responsible for a spectrum of smooth muscle disease. ACTG2 encodes γ2 enteric actin and is the first gene to be clearly associated with MMIHS, suggesting an important role for contractile proteins in enteric smooth muscle disease.

Phenotypic expansion of visceral myopathy associated with ACTG2 tandem base substitution

“…6,7 On the other hand, ACTG2 was recently found mutated in a family with FVM and adult gastrointestinal problems, 14 as well as in the MMIH syndrome with severe neonatal symptoms from the intestines and the urinary tract. 15,16 The family investigated in this study shows a phenotypic overlap with both FVM and the MMIH syndrome but our observations on the variable onset as well as the involvement of the bile tract and uterus add to previous reports. We initially considered genetic heterogeneity and performed WES on four affected family members.…”

“…This is supported by the accidental finding of a nonsense variant c.187C4T (p.Arg63*) in ACTG2 in a single individual out of 1900 control subjects. 16 The carrier of the truncating variant had mild constipation that did not require any medical treatment.…”

“…[12][13][14][15] In contrast, milder forms of enteric visceral myopathy may remain undiagnosed until adulthood. 14,16 Because of the variable symptomatology, this group of visceral myopathies constitutes a diagnostic challenge and some adult patients are referred to as chronic pseudo-obstruction, hollow visceral myopathy or pseudoHirschprung disease. 2,17 The findings on pathogenic MYH11 and ACTA2 variants in TAAD have raised the possibility that different components of the smooth muscle contractile unit and cytoskeleton may be responsible for other types of myopathies.…”

“…More recent studies identified several heterozygous missense variants in ACTG2 in MMIH patients that had occurred de novo or were inherited. 15,16 Notably, all disease-associated variants in ACTG2 identified to date predict missense substitutions and the absence of loss-of-function variants in affected individuals has led to the suggestion of a dominant-negative effect in FVM. 16 We investigated a large Swedish family segregating FVM with symptoms from the intestines, the urinary tract and the biliary tract, as well as the uterus.…”

“…15,16 Notably, all disease-associated variants in ACTG2 identified to date predict missense substitutions and the absence of loss-of-function variants in affected individuals has led to the suggestion of a dominant-negative effect in FVM. 16 We investigated a large Swedish family segregating FVM with symptoms from the intestines, the urinary tract and the biliary tract, as well as the uterus. Whole-exome sequencing (WES) revealed a novel heterozygous tandem base substitution (TBS) in ACTG2 in all affected family members and further analysis supported a dominantnegative mechanism of the mutated actin.…”