2.1 Intestinal pseudo-obstruction

Several inherited mutations in the ACTG2 gene have been identified in people with intestinal pseudo-obstruction, a condition that impairs the smooth muscle contractions that move food through the digestive tract (peristalsis). This condition mimics a physical blockage of the intestines without an actual obstruction. Problems with emptying the bladder can also occur in people with this disorder.

The ACTG2 gene mutations that cause intestinal pseudo-obstruction are thought to hinder the formation of actin filaments in the cytoskeleton and reduce the ability of smooth muscles in the intestines and bladder to contract. As a result, peristalsis in the intestines is impaired and the bladder is less able to contract and expel urine, leading to the signs and symptoms of this condition.

2.2 Megacystis-microcolon-intestinal hypoperistalsis syndrome

At least 22 ACTG2 gene mutations have been found to cause megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), which is characterized by impairment of peristalsis and emptying the bladder.

The ACTG2 gene mutations that cause MMIHS are not inherited; rather they occur as a random (de novo) event during the formation of reproductive cells (eggs or sperm) or in early embryonic development. The alterations change single protein building blocks (amino acids) in the γ-2 actin protein. These changes hinder the formation of actin filaments and reduce the ability of smooth muscles in the bladder and intestines to contract. As a result, the bladder cannot empty normally, leading to an enlarged bladder (megacystis) and painful abdominal swelling (distention). In addition, partially digested food can build up in the intestines, which also contributes to distention. Poor digestion may lead to malnutrition in people with MMIHS.

2.3 Other disorders

ACTG2 gene mutations cause a spectrum of disorders (sometimes referred to as ACTG2-related disorders), with MMIHS (described above) at the severe end. As in MMIHS, most of these mutations change single amino acids in the γ-2 actin protein. However, in less severely affected individuals, the mutations are usually inherited. These mutations often cause intestinal pseudo-obstruction (described above). In some affected individuals, the smooth muscle problems are episodic and come and go throughout life. Intestinal malrotation can also occur in people with ACTG2 gene mutations. This condition occurs when the intestines do not fold properly; instead, they twist abnormally, which can impede the movement of food. Effects on the urinary tract include recurrent urinary tract infections and impaired bladder function. Individuals with inherited ACTG2 gene mutations can have one or more of these intestinal or urinary tract abnormalities; they are usually milder than MMIHS, or they begin later in life. It is unclear why inherited and de novo mutations result in conditions with different severities.