title: ACTG2 variants impair actin polymerization in sporadic Megacystis Microcolon Intestinal Hypoperistalsis Syndrome.
abstract: Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIHS) is a rare congenital disorder, in which heterozygous missense variants in the Enteric Smooth Muscle actin γ-2 (ACTG2) gene have been recently identified. To investigate the mechanism by which ACTG2 variants lead to MMIHS, we screened a cohort of eleven MMIHS patients, eight sporadic and three familial cases, and performed immunohistochemistry, molecular modeling and molecular dynamics (MD) simulations, and in vitro assays. In all sporadic cases, a heterozygous missense variant in ACTG2 was identified. ACTG2 expression was detected in all intestinal layers where smooth muscle cells are present in different stages of human development. No histopathological abnormalities were found in the patients. Using molecular modeling and MD simulations, we predicted that ACTG2 variants lead to significant changes to the protein function. This was confirmed by in vitro studies, which showed that the identified variants not only impair ACTG2 polymerization, but also contribute to reduced cell contractility. Taken together, our results confirm the involvement of ACTG2 in sporadic MMIHS, and bring new insights to MMIHS pathogenesis.
authors.affiliation: Department of Clinical Genetics.
authors.forename: Danny
authors.initials: D
authors.lastname: Halim
authors.affiliation: Department of Clinical Genetics, Birth Defects Research Centre, UCL Institute of Child Health, London, UK.
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
authors.affiliation: Department of Cell Biology.
authors.forename: Luca
authors.initials: L
authors.lastname: Signorile
authors.affiliation: Department of Pathology, and.
authors.forename: Rob M
authors.initials: RM
authors.lastname: Verdijk
authors.affiliation: Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Christine S
authors.initials: CS
authors.lastname: van der Werf
authors.affiliation: Department of Clinical Genetics.
authors.forename: Yunia
authors.initials: Y
authors.lastname: Sribudiani
authors.affiliation: Erasmus Center for Biomics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Rutger W W
authors.initials: RW
authors.lastname: Brouwer
authors.affiliation: Erasmus Center for Biomics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Wilfred F J
authors.initials: WF
authors.lastname: van IJcken
authors.affiliation: Department of Immunology, Genetics and Pathology, Medical Genetics and Genomics, Uppsala University, Uppsala, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Dahl
authors.affiliation: Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Joke B G M
authors.initials: JB
authors.lastname: Verheij
authors.affiliation: Unité de Génétiqué Clinique, and.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Baumann
authors.affiliation: Lucile Salter Packard Children's Hospital, Stanford University, Palo Alto, CA, USA and.
authors.forename: John
authors.initials: J
authors.lastname: Kerner
authors.affiliation: Department of Clinical Genetics.
authors.forename: Yolande
authors.initials: Y
authors.lastname: van Bever
authors.affiliation: Department of Cell Biology.
authors.forename: Niels
authors.initials: N
authors.lastname: Galjart
authors.affiliation: Department of Pediatric Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Rene M H
authors.initials: RM
authors.lastname: Wijnen
authors.affiliation: Department of Pediatric Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.affiliation: Department of Clinical Genetics, Birth Defects Research Centre, UCL Institute of Child Health, London, UK.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Burns
authors.affiliation: Biochimie Prenatalé, Hôpital Universitaire Robert Debré, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Muller
authors.affiliation: Department of Clinical Genetics.
authors.forename: Alice S
authors.initials: AS
authors.lastname: Brooks
authors.affiliation: Department of Clinical Genetics, m.alves@erasmusmc.nl.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Alves
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000199:Actins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D003106:Colon / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D017809:Fatal Outcome; D005260:Female; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D007413:Intestinal Mucosa / Q000378:metabolism*; D007418:Intestinal Pseudo-Obstruction / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007422:Intestines / Q000473:pathology; D008297:Male; D056004:Molecular Dynamics Simulation; D009119:Muscle Contraction / Q000235:genetics*; D009130:Muscle, Smooth / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D010375:Pedigree; D055503:Protein Multimerization; D001743:Urinary Bladder / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: C579475:ACTG2 protein, human; D000199:Actins