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-microcolon-intestinal 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.

Figure 1

Pedigree of the Swedish family segregating FVM and a TBS in ACTG2. (a) The genotype at cDNA positions 806–807 of ACTG2 is shown below each symbol (GC, wild-type allele; AA, disease-associated allele). Affected individuals are shown with black filled symbols. Ind. I:2 with suspected disease is shown in gray. Asterisks denote subjects analyzed by WES. (b) Chromatogram of part of the ACTG2 transcript from fibroblasts in the affected ind. III:9 showing expression of the wild-type (GC) and the mutated transcripts (AA) at cDNA positions 806–807.

Figure 2

Structural protein model of wt and mutated ACTG2. Selected part of the ACTG2 model highlighting residue 269 in the actin monomer (light gray) and its relative position to the adjacent actin monomer (deep gray) in the actin polymer. The left panel shows the wt residue Gly269 in close proximity to residues 204, 64 and 60 of the neighboring actin monomer (3.91 Å from Thr204, 7.49 Å from Gly64 and 9.47 Å from Gln60, respectively). The right panel shows the missense variant Glu269 and its side chain that extends further out from the loop. Glutamic acid at position 269 alters distances (and charge) with respect to the closest residues in the neighboring actin monomer (4.44 Å from Thr204, 9.31 Å from Gln64 and 11.05 Å from Gln60, respectively), suggesting an effect on actin monomer interactions.