Abstract
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.
Highlights
Berdon first described patients with a severe phenotype characterized by smooth muscle functional failure in 1976, at a time when total parenteral nutrition (TPN) was becoming common clinical practice [1]
Berdon noted that because the functional intestinal defect could not be corrected, finding the cause of the disorder described as megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS, OMIM 249210) would be necessary to avoid keeping patients with the disorder as ‘‘prisoners’’ of TPN without otherwise effective treatments
Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is characterized by prenatal bladder enlargement, neonatal functional gastrointestinal obstruction, and chronic dependence on total parenteral nutrition (TPN) and urinary catheterization [2,3,4]
Summary
Berdon first described patients with a severe phenotype characterized by smooth muscle functional failure in 1976, at a time when total parenteral nutrition (TPN) was becoming common clinical practice [1]. Berdon noted that because the functional intestinal defect could not be corrected, finding the cause of the disorder described as megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS, OMIM 249210) would be necessary to avoid keeping patients with the disorder as ‘‘prisoners’’ of TPN without otherwise effective treatments. Genetic, pathologic, endocrine, and physiologic studies have sought to determine the cause of MMIHS without success, and the clinical history of patients with these disorders often fulfills Berdon’s prediction as patients remain on long-term TPN, and the underlying etiology remains unknown. MMIHS is characterized by prenatal bladder enlargement, neonatal functional gastrointestinal obstruction, and chronic dependence on total parenteral nutrition (TPN) and urinary catheterization [2,3,4]. The first challenge in understanding the genetics of MMIHS has been in Author Summary
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