title: Segregation of a missense variant in enteric smooth muscle actin γ-2 with autosomal dominant familial visceral myopathy.
abstract: OBJECTIVE
  Familial visceral myopathy (FVM) is a rare inherited form of myopathic pseudo-obstruction; little is known about the genetic factors that cause this disorder. FVM is characterized by impaired functions of enteric smooth muscle cells, resulting in abnormal intestinal motility, severe abdominal pain, malnutrition, and even death. We searched for genetic factors that might cause this disorder.
  
  
  METHODS
  We performed whole-exome sequence analysis of blood samples from 2 individuals in a family that had 7 members diagnosed with FVM. Sanger sequencing was used to analyze additional family members and 280 individuals without this disorder (controls). Intestinal tissue samples from 4 patients and 2 controls were analyzed by immunohistochemistry. Functional studies, including immunofluorescence, cell contractility, and actomyosin structure analyses, were performed using CRL-1976 and U2OS sarcoma cell lines.
  
  
  RESULTS
  Whole-exome sequence analysis of DNA from 2 siblings identified 83 gene variants that were shared between the siblings and considered as possible disease-causing changes. A heterozygous variant, R148S in enteric smooth muscle actin γ-2 (ACTG2), segregated with disease phenotype. Intestinal smooth muscle (muscularis propria) from individuals with FVM had reduced levels of cytoplasmic ACTG2 and abnormal accumulation of the protein into intracellular inclusions compared with controls. Sarcoma cells that expressed exogenous ACTG2(R148S) incorporated reduced amounts of this protein into actin filaments compared with cells expressing ACTG2(wt) (P < .001). ACTG2(R148S) also interfered with actin cytoskeleton organization and the contractile activities of the cells, indicating a dominant-negative effect. These findings, along with the site of the variation in the protein, indicate that ACTG2 R148S interferes with actin filament assembly.
  
  
  CONCLUSIONS
  We identified the R148S variant in ACTG2 as a cause of FVM in one family. The altered ACTG2 protein appears to aggregate, rather than form actin filaments, in intestinal smooth muscle tissue. This defect could impair contraction of the visceral smooth muscle cells and reduce bowel motility.
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Heli J
authors.initials: HJ
authors.lastname: Lehtonen
authors.forename: Taina
authors.initials: T
authors.lastname: Sipponen
authors.forename: Sari
authors.initials: S
authors.lastname: Tojkander
authors.forename: Riitta
authors.initials: R
authors.lastname: Karikoski
authors.forename: Heikki
authors.initials: H
authors.lastname: Järvinen
authors.forename: Nigel G
authors.initials: NG
authors.lastname: Laing
authors.forename: Pekka
authors.initials: P
authors.lastname: Lappalainen
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
authors.forename: Sari
authors.initials: S
authors.lastname: Tuupanen
mesh_terms: D000199:Actins / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D020090:Chromosome Segregation / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D005387:Finland; D005769:Gastrointestinal Motility / Q000502:physiology; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007418:Intestinal Pseudo-Obstruction / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D007422:Intestines / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000378:metabolism* / Q000503:physiopathology; D020125:Mutation, Missense / Q000235:genetics*; D009197:Myenteric Plexus / Q000002:abnormalities / Q000378:metabolism / Q000503:physiopathology; D010375:Pedigree; D010641:Phenotype
chemical_list: C579475:ACTG2 protein, human; D000199:Actins