Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome.

PLoS Genetics. 2014;10(3):e1004258 DOI 10.1371/journal.pgen.1004258


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Journal Title: PLoS Genetics

ISSN: 1553-7390 (Print); 1553-7404 (Online)

Publisher: Public Library of Science (PLoS)

LCC Subject Category: Science: Biology (General): Genetics

Country of publisher: United States

Language of fulltext: English

Full-text formats available: PDF, HTML, XML



Michael F Wangler
Claudia Gonzaga-Jauregui
Tomasz Gambin
Samantha Penney
Timothy Moss
Atul Chopra
Frank J Probst
Fan Xia
Yaping Yang
Steven Werlin
Ieva Eglite
Liene Kornejeva
Carlos A Bacino
Dustin Baldridge
Jeff Neul
Efrat Lev Lehman
Austin Larson
Joke Beuten
Donna M Muzny
Shalini Jhangiani
Baylor-Hopkins Center for Mendelian Genomics
Richard A Gibbs
James R Lupski
Arthur Beaudet


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Time From Submission to Publication: 26 weeks


Abstract | Full Text

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.