title: De novo ACTG2 mutations cause congenital distended bladder, microcolon, and intestinal hypoperistalsis.
abstract: Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is characterized by prenatal-onset distended urinary bladder with functional intestinal obstruction, requiring extensive surgical intervention for survival. While it is believed to be an autosomal recessive disorder, most cases are sporadic. Through whole-exome sequencing in a child with MMIHS, we identified a de novo mutation, p.R178L, in the gene encoding the smooth muscle gamma-2 actin, ACTG2. We subsequently detected another de novo ACTG2 mutation, p.R178C, in an additional child with MMIHS. Actg2 transcripts were primarily found in murine urinary bladder and intestinal tissues. Structural analysis and functional experiments suggested that both ACTG2 mutants interfere with proper polymerization of ACTG2 into thin filaments, leading to impaired contractility of the smooth muscle. In conclusion, our study suggests a pathogenic mechanism for MMIHS by identifying causative ACTG2 mutations.
authors: Dr. John T. Macdonald Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, 1501 NW 10th Avenue, BRB-610 (M-860), Miami, FL, 33136, USA.
authors: Willa
authors: W
authors: Thorson
authors: Oscar
authors: O
authors: Diaz-Horta
authors: Joseph
authors: J
authors: Foster
authors: Michail
authors: M
authors: Spiliopoulos
authors: Rubén
authors: R
authors: Quintero
authors: Amjad
authors: A
authors: Farooq
authors: Susan
authors: S
authors: Blanton
authors: Mustafa
authors: M
authors: Tekin
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000199:Actins / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003106:Colon / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D007418:Intestinal Pseudo-Obstruction / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010375:Pedigree; D001743:Urinary Bladder / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology
chemical_list: C579475:ACTG2 protein, human; D000199:Actins