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

TitleHeterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome.
Publication TypeJournal Article
Year of Publication2014
AuthorsWangler, 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, ELev, Larson, A, Beuten, J, Muzny, DM, Jhangiani, S, Gibbs, RA, Lupski, JR, Beaudet, A
Corporate Authors
JournalPLoS Genet
Volume10
Issue3
Paginatione1004258
Date Published2014 Mar
ISSN1553-7404
KeywordsAbnormalities, Multiple, Actins, Adolescent, Adult, Child, Child, Preschool, Colon, Exome, Female, Heterozygote, Humans, Intestinal Pseudo-Obstruction, Male, Muscle, Smooth, Mutation, Urinary Bladder
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.

DOI10.1371/journal.pgen.1004258
Alternate JournalPLoS Genet.
PubMed ID24676022
PubMed Central IDPMC3967950
Grant ListK08 NS076547 / NS / NINDS NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
T32 GM007526 / GM / NIGMS NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
NS076547 / NS / NINDS NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States