A heterozygous variant in enteric smooth muscle actin γ-2 (ACTG2) can cause familial visceral myopathy (FVM), according to the December issue of Gastroenterology. The altered gene product appears to aggregate, rather than form actin filaments, in intestinal smooth muscle cells, disrupting their contraction and reducing bowel motility.
FVM is a rare condition in which the duodenum is dilated and the intestinal muscles don’t function normally. It affects the movement of digestive material through the intestines, and symptoms are similar to those caused by an intestinal obstruction. FVM is characterized by impaired functions of enteric smooth muscle cells, resulting in abnormal intestinal motility, severe abdominal pain, malnutrition, and even death. Although the disease is inherited, no genetic cause has been identified.
Heli Lehtonen et al. searched for genetic factors that might cause the disease, sequencing DNA from 2 individuals in a family that had 7 members with disease, along with DNA from additional family members and 280 individuals without this disorder (controls).
Lehtonen et al. identified a heterozygous variant, encoding the amino acid change R148S, in ACTG2; the variant segregated with disease phenotype. Intestinal smooth muscle from individuals with FVM had reduced levels of cytoplasmic ACTG2, and the authors observed abnormal accumulation of the protein into intracellular inclusions, compared with controls.
When Lehtonen et al. expressed the disease-associated variant in sarcoma cells, they found reduced amounts of the protein incorporated into actin filaments, compared with cells that express the non-disease associated form. ACTG2R148S also interfered with actin cytoskeleton organization and the contractile activities of the cells, indicating a dominant-negative effect (see below figure).
These findings, along with the site of the variation in the protein, indicate that ACTG2R148S interferes with actin filament assembly.
Actin polymerizes into filaments that provide force for cell shape changes, movement, and other important processes. The actin filaments, together with myosin II, form diverse contractile structures such as the myofibrils in muscle cells and stress fibers of non-muscle cells.
Until now, specific variants in all actins except ACTG2 have been linked to a human disease. ACTC1 (cardiac smooth muscle actin) variants have been associated with dilated cardiomyopathy and hypertrophic cardiomyopathy. Autosomal dominant hearing loss has been reported in carriers of missense variants of ACTG1 (g-actin 1). A missense variant (R183W) in non-muscle actin (ACTB, β-actin) has been linked to a combination of malformations, sensory hearing loss, and delayed-onset generalized dystonia. Inherited missense variants in aortic smooth muscle cell actin (ACTA2, commonly known as α-SMA) can cause a variety of vascular diseases such as strokes, thoracic aortic aneurysms and dissections, and early-onset coronary artery disease.
Lehtonen et al. propose that the poor incorporation of the ACTG2R148S into actin filaments caused defects in the assembly of actomyosin bundles and thereby the function of the muscular layer of the intestine, disrupting intestinal motility.
In an editorial that accompanies the article, Peter Rubenstein and Emeran Mayer state the need for a model system in which a single mutant actin species can be expressed and purified in quantities sufficient for biochemical analyses. They add that it would also be beneficial to be able to study the effect of the mutation in cells that express only the mutant actin so the undiluted effect of the mutation can be observed.
Lehtonen et al. state that although ACTG2 variants appear to cause a subset of familial cases of visceral myopathy, other loci should be considered. Formation, regulation, and turnover of actin filament structures require more than 100 accessory proteins. Defects in any of these might be linked to abnormal cytoskeletal structure and contractility of intestinal smooth muscle cells.
Lehtonen et al. state that despite the rarity of the visceral myopathies, further work is required to examine additional families, identify other factors that might cause FVM, and determine the contribution of de novo ACTG2 variants in cases of sporadic CIP.
Read the article online.
Lehtonen HJ, Sipponen T, Tojkander S, et al. Segregation of a missense variant in enteric smooth muscle actin γ-2 with autosomal dominant familial visceral myopathy. Gastroenterology 2012;143:1482-1491.e3.
Read the accompanying editorial.
Rubenstein PA and Mayer EA. Familial visceral myopathies: from symptom-based syndromes to actin-related diseases. Gastroenterology 2012;143:1420-1423.