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PLoS Genet. 2014 Mar 27;10(3):e1004258. doi: 10.1371/journal.pgen.1004258. eCollection 2014 Mar.

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

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America; Texas Children's Hospital, Houston, Texas, United States of America.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
3
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America; Institute of Computer Science, Warsaw University of Technology, Warsaw, Poland.
4
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
5
Children's Clinical University Hospital, Riga, Latvia.
6
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America; Texas Children's Hospital, Houston, Texas, United States of America; Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
7
Department of Genetics, Children's Hospital Colorado, Aurora, Colorado.
8
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
9
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.

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.

PMID:
24676022
PMCID:
PMC3967950
DOI:
10.1371/journal.pgen.1004258
[Indexed for MEDLINE]
Free PMC Article

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