Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice
| Autor: | Dick Tibboel, Wei Yan, Rutger W W Brouwer, Tono Djuwantono, Qing Lyu, Alice S. Brooks, Erwin Brosens, Alan J. Burns, Karen L. de Mesy Bentley, Joke B. G. M. Verheij, Hans J. Stoop, Suowen Xu, Christine K. Christie, Maria M. Alves, Joseph M. Miano, Daniel Oliver, Orazio J. Slivano, Vivek Nanda, Wilfred F. J. van IJcken, Zheng Gen Jin, Michael Doukas, Michael P. Wilson, Danny Halim, Robert M.W. Hofstra, Yu Han |
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| Přispěvatelé: | Clinical Genetics, Pathology, Cell biology, Pediatric Surgery |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Muscle Proteins TROPOMODULIN MOUSE EMBRYOGENESIS Autoantigens smooth muscle Mice Nemaline myopathy LEIOMODIN Myosin genetics Multidisciplinary Smooth muscle contraction FAMILY PNAS Plus Codon Nonsense LIGHT-CHAIN KINASE Female MYOSIN medicine.symptom CRISPR-Cas9 Muscle Contraction myopathy EXPRESSION medicine.medical_specialty ACTA2 MUTATION Colon Urinary Bladder Biology Filamentous actin 03 medical and health sciences Internal medicine medicine Animals Humans Abnormalities Multiple Myopathy Actin Intestinal Pseudo-Obstruction Infant Newborn Muscle Smooth NEMALINE MYOPATHY Megacystis Microcolon medicine.disease Molecular biology GENE Cytoskeletal Proteins 030104 developmental biology Endocrinology |
| Zdroj: | Proceedings of the National Academy of Sciences of the U.S.A., 114(13), E2739-E2747. National Academy of Sciences Proceedings of the National Academy of Science of the United States of America, 114(13), E2739-E2747. NATL ACAD SCIENCES |
| ISSN: | 0027-8424 |
| Popis: | 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 in Leiomodin1 (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 of Lmod1 to 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 define LMOD1 as a disease gene for MMIHS and suggest its role in establishing normal smooth muscle cytoskeletal-contractile coupling. |
| Databáze: | OpenAIRE |
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