title: Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice.
abstract: Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a congenital visceral myopathy characterized by severe dilation of the urinary bladder and defective intestinal motility. The genetic basis of MMIHS has been ascribed to spontaneous and autosomal dominant mutations in actin gamma 2 (ACTG2), a smooth muscle contractile gene. However, evidence suggesting a recessive origin of the disease also exists. Using combined homozygosity mapping and whole exome sequencing, a genetically isolated family was found to carry a premature termination codon inLeiomodin1(LMOD1), a gene preferentially expressed in vascular and visceral smooth muscle cells. Parents heterozygous for the mutation exhibited no abnormalities, but a child homozygous for the premature termination codon displayed symptoms consistent with MMIHS. We used CRISPR-Cas9 (CRISPR-associated protein) genome editing ofLmod1to generate a similar premature termination codon. Mice homozygous for the mutation showed loss of LMOD1 protein and pathology consistent with MMIHS, including late gestation expansion of the bladder, hydronephrosis, and rapid demise after parturition. Loss of LMOD1 resulted in a reduction of filamentous actin, elongated cytoskeletal dense bodies, and impaired intestinal smooth muscle contractility. These results defineLMOD1as a disease gene for MMIHS and suggest its role in establishing normal smooth muscle cytoskeletal-contractile coupling.
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands.
authors.forename: Danny
authors.initials: D
authors.lastname: Halim
authors.affiliation: Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Wilson
authors.affiliation: Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557.
authors.forename: Daniel
authors.initials: D
authors.lastname: Oliver
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands.
authors.forename: Erwin
authors.initials: E
authors.lastname: Brosens
authors.affiliation: Department of Genetics, University Medical Center, University of Groningen, 9700 RB Groningen, The Netherlands.
authors.forename: Joke B G M
authors.initials: JB
authors.lastname: Verheij
authors.affiliation: Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
authors.forename: Yu
authors.initials: Y
authors.lastname: Han
authors.affiliation: Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
authors.forename: Vivek
authors.initials: V
authors.lastname: Nanda
authors.affiliation: Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lyu
authors.affiliation: Department of Pathology, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands.
authors.forename: Michael
authors.initials: M
authors.lastname: Doukas
authors.affiliation: Department of Pathology, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Stoop
authors.affiliation: Center for Biomics, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands.
authors.forename: Rutger W W
authors.initials: RW
authors.lastname: Brouwer
authors.affiliation: Center for Biomics, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands.
authors.forename: Wilfred F J
authors.initials: WF
authors.lastname: van IJcken
authors.affiliation: Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
authors.forename: Orazio J
authors.initials: OJ
authors.lastname: Slivano
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands.|Stem Cells and Regenerative Medicine, Birth Defects Research Centre, University College London Institute of Child Health, London WC1N 1EH, United Kingdom.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Burns
authors.affiliation: Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
authors.forename: Christine K
authors.initials: CK
authors.lastname: Christie
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
authors.forename: Karen L
authors.initials: KL
authors.lastname: de Mesy Bentley
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands.
authors.forename: Alice S
authors.initials: AS
authors.lastname: Brooks
authors.affiliation: Department of Pediatric Surgery, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.affiliation: Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
authors.forename: Suowen
authors.initials: S
authors.lastname: Xu
authors.affiliation: Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
authors.forename: Zheng Gen
authors.initials: ZG
authors.lastname: Jin
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
authors.forename: Tono
authors.initials: T
authors.lastname: Djuwantono
authors.affiliation: Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557.
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Alves
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands; j.m.miano@rochester.edu r.hofstra@erasmusmc.nl.|Stem Cells and Regenerative Medicine, Birth Defects Research Centre, University College London Institute of Child Health, London WC1N 1EH, United Kingdom.
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
authors.affiliation: Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; j.m.miano@rochester.edu r.hofstra@erasmusmc.nl.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Miano
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018389:Codon, Nonsense; D003106:Colon / Q000002:abnormalities*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007418:Intestinal Pseudo-Obstruction / Q000235:genetics*; D051379:Mice; D009119:Muscle Contraction / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009130:Muscle, Smooth / Q000502:physiology; D001743:Urinary Bladder / Q000002:abnormalities*
chemical_list: D001324:Autoantigens; D018389:Codon, Nonsense; D003598:Cytoskeletal Proteins; C103926:LMOD1 protein, human; D009124:Muscle Proteins; C523689:leiomodin protein, mouse
keywords: CRISPR-Cas9; Leiomodin; genetics; myopathy; smooth muscle