1. Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice
- Author
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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, Clinical Genetics, Pathology, Cell biology, and Pediatric Surgery
- Subjects
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 - 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 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.
- Published
- 2017