Medical College of Wisconsin
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Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome. PLoS Genet 2014 Mar;10(3):e1004258

Date

03/29/2014

Pubmed ID

24676022

Pubmed Central ID

PMC3967950

DOI

10.1371/journal.pgen.1004258

Scopus ID

2-s2.0-84897420283 (requires institutional sign-in at Scopus site)   126 Citations

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.

Author List

Wangler MF, Gonzaga-Jauregui C, Gambin T, Penney S, Moss T, Chopra A, Probst FJ, Xia F, Yang Y, Werlin S, Eglite I, Kornejeva L, Bacino CA, Baldridge D, Neul J, Lehman EL, Larson A, Beuten J, Muzny DM, Jhangiani S, Baylor-Hopkins Center for Mendelian Genomics, Gibbs RA, Lupski JR, Beaudet A

Author

Steven L. Werlin MD Emeritus Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Abnormalities, Multiple
Actins
Adolescent
Adult
Child
Child, Preschool
Colon
Exome
Female
Heterozygote
Humans
Intestinal Pseudo-Obstruction
Male
Muscle, Smooth
Mutation
Urinary Bladder