Phenotypic expansion of visceral myopathy associated with ACTG2 tandem base substitution

Abstract

Familial visceral myopathy (FVM) is a rare heritable and heterogeneous condition due to impaired smooth muscle function. We identified a family segregating 11 individuals with a spectrum of visceral symptoms involving the small intestine, colon, biliary tract, urinary tract and uterus. Whole-exome sequencing revealed a novel heterozygous tandem base substitution c.806_807delinsAA (p.(Gly269Glu)) in ACTG2, encoding smooth muscle actin γ-2, in affected family members. Variants in ACTG2 were recently identified in FVM with intestinal pseudo-obstruction as well as with the congenital megacystics-microcolonintestinal hypoperistalsis syndrome. In our family, eight affected members presented with severe complications from the biliary and/or the urinary tracts in addition to gastrointestinal pseudo-obstructions. Furthermore, all affected mothers had a history of assisted deliveries owing to poor progress during labor and weak uterine contractions. The variable involvement of multiple smooth muscle-dependent organs in our family, including the biliary tract and the uterus, add to the phenotypic spectrum associated with ACTG2 missense variants.

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

“…Significant intrafamilial variability was observed accounting for this observation as the siblings inherited a pathogenic variant in ACTG2 from their mother who had been undiagnosed. Notably, she had prolonged labor due to uterine atony, a feature also reported in another family (Fam51) in the cohort as well as other cases in the literature (Klar et al, ; Sipponen, Karikoski, Nuutinen, Markkola, & Kaitila, ). In an additional family with multiple affected members (Fam34) symptoms ranged from chronic constipation with or without urinary tract infections to severely affected individuals requiring catheterizations and abdominal surgeries (Figure S4a).…”

“…We and others identified ACTG2 as the first single gene for the disease traits of visceral myopathy (Lehtonen et al, ), and MMIHS/CIPO (Thorson et al, ; Wangler et al, ). Subsequent reports, supported by functional data from mouse models, established the important role of ACTG2 in these disorders (Halim et al, ; Holla, Bock, Busk, & Isfoss, ; Klar et al, ; Lu et al, ; Matera et al, ; Milunsky, Baldwin, et al, ; Milunsky, Lazier, et al, ; Moreno et al, ; Tuzovic et al, ; Whittington, Poole, Dutta, & Munn, ). ACTG2 encodes a muscle actin isoform predominantly expressed in the intestinal smooth muscle (Miwa et al, ; Szucsik & Lessard, ) which, together with myosin, comprises the apparatus responsible for muscle contraction and relaxation.…”

Variants of the ACTG2 gene correlate with degree of severity and presence of megacystis in chronic intestinal pseudo-obstruction

“…On the other hand, no anomaly of muscle layers was reported in a patient affected by visceral myopathy and carrying a p.(Gly269Glu) ACTG2 variant. 11 In addition, cell experimental studies with ACTG2 variant constructs revealed reduced incorporation of the variant protein into actin filaments 7 and confocal images allowed to assess a poor association of ACTG2 mutant fibers with actin filaments, 9 thus suggesting again a dominant negative effect of the ACTG2 variants.…”

“…5,6 Variants of the ACTG2 gene, encoding gamma 2 enteric actin, a protein crucial for correct enteric muscle contraction, have been found in CIPO patients affected with congenital or late-onset visceral myopathy or, alternatively, megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS). [7][8][9][10][11][12] Here we report a study, carried out by whole exome sequencing (WES) and targeted Sanger sequencing in a total of 33 CIPO patients, which has allowed to define part of the phenotypic spectrum associated with ACTG2 defects.…”

Familial chronic megacolon presenting in childhood or adulthood: Seeking the presumed gene association

“…As chronic megacolon is associated with increased colonic compliance, it is also relevant to assess genes associated with smooth muscle development which may result in hypoperistalsis. Mutations in the actin ( ACTG2 ) gene are associated with pseudo‐obstruction, microcolon, megacystis and may result from missense mutations at arginine residues or mutations p.R178L and p.R178C, or p.(Gly269Glu) in ACTG2 …”