title: Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome.
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.
authors.affiliation: 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.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wangler
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gonzaga-Jauregui
authors.affiliation: 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.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Samantha
authors.initials: S
authors.lastname: Penney
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Timothy
authors.initials: T
authors.lastname: Moss
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Atul
authors.initials: A
authors.lastname: Chopra
authors.affiliation: 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.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Probst
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Fan
authors.initials: F
authors.lastname: Xia
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: Steven
authors.initials: S
authors.lastname: Werlin
authors.affiliation: Children's Clinical University Hospital, Riga, Latvia.
authors.forename: Ieva
authors.initials: I
authors.lastname: Eglite
authors.affiliation: Children's Clinical University Hospital, Riga, Latvia.
authors.forename: Liene
authors.initials: L
authors.lastname: Kornejeva
authors.affiliation: 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.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Bacino
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Dustin
authors.initials: D
authors.lastname: Baldridge
authors.affiliation: 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.
authors.forename: Jeff
authors.initials: J
authors.lastname: Neul
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Efrat Lev
authors.initials: EL
authors.lastname: Lehman
authors.affiliation: Department of Genetics, Children's Hospital Colorado, Aurora, Colorado.
authors.forename: Austin
authors.initials: A
authors.lastname: Larson
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Joke
authors.initials: J
authors.lastname: Beuten
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Shalini
authors.initials: S
authors.lastname: Jhangiani
authors.affiliation: 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.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: 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.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: 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.
authors.forename: Arthur
authors.initials: A
authors.lastname: Beaudet
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000199:Actins / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003106:Colon / Q000002:abnormalities* / Q000473:pathology; D059472:Exome; D005260:Female; D006579:Heterozygote; D006801:Humans; D007418:Intestinal Pseudo-Obstruction / Q000235:genetics* / Q000473:pathology; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D001743:Urinary Bladder / Q000002:abnormalities* / Q000473:pathology
chemical_list: C579475:ACTG2 protein, human; D000199:Actins