Heterozygous De Novo and Inherited Mutations in the Smooth Muscle Actin ( ACTG2) Gene Underlie Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome

摘要

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare disorder of enteric smooth muscle function affecting the intestine and bladder. Patients with this severe phenotype are dependent on total parenteral nutrition and urinary catheterization. The cause of this syndrome has remained a mystery since Berdon's initial description in 1976. No genes have been clearly linked to MMIHS. We used whole-exome sequencing for gene discovery followed by targeted Sanger sequencing in a cohort of patients with MMIHS and intestinal pseudo-obstruction. We identified heterozygous ACTG2 missense variants in 15 unrelated subjects, ten being apparent de novo mutations. Ten unique variants were detected, of which six affected CpG dinucleotides and resulted in missense mutations at arginine residues, perhaps related to biased usage of CpG containing codons within actin genes. We also found some of the same heterozygous mutations that we observed as apparent de novo mutations in MMIHS segregating in families with intestinal pseudo-obstruction, suggesting that ACTG2 is responsible for a spectrum of smooth muscle disease. ACTG2 encodes γ2 enteric actin and is the first gene to be clearly associated with MMIHS, suggesting an important role for contractile proteins in enteric smooth muscle disease. Author Summary In 1976, a radiologist, Walter Berdon described a group of patients with a rare intestinal and bladder disorder in which the smooth muscle of those organs failed to contract. These patients are unable to digest food, require multiple abdominal surgeries and are diagnosed with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS). Since the description of MMIHS, the genes that cause it have remained a mystery. We followed and obtained DNA from patients with this disorder over a period of over 14 years and assembled a large group of cases. We used whole-exome sequencing, a powerful tool used to identify disease genes, and found mutations in ACTG2 , a visceral actin gene. Actins are components of muscle contractile units, and one Finnish family has been previously found with less severe gastrointestinal problems due to mutations in this gene. In our patients, we find de novo mutations in the majority of cases of MMIHS. However, we also find families with the disease over several generations due to these same mutations. This work provides the first disease gene for MMIHS, and suggests new treatment options.