Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice

Proc Natl Acad Sci U S A. 2017 Mar 28;114(13):E2739-E2747. doi: 10.1073/pnas.1620507114.

Danny Halim ¹, Michael P Wilson ², Daniel Oliver ³, Erwin Brosens ¹, Joke B G M Verheij ⁴, Yu Han ², Vivek Nanda ², Qing Lyu ², Michael Doukas ⁵, Hans Stoop ⁵, Rutger W W Brouwer ⁶, Wilfred F J van IJcken ⁶, Orazio J Slivano ², Alan J Burns ¹ ⁷, Christine K Christie ², Karen L de Mesy Bentley ⁸, Alice S Brooks ¹, Dick Tibboel ⁹, Suowen Xu ², Zheng Gen Jin ², Tono Djuwantono ¹⁰, Wei Yan ³, Maria M Alves ¹, Robert M W Hofstra ¹¹ ⁷, Joseph M Miano ¹²

Affiliations

1 Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands.
2 Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
3 Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557.
4 Department of Genetics, University Medical Center, University of Groningen, 9700 RB Groningen, The Netherlands.
5 Department of Pathology, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands.
6 Center for Biomics, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands.
7 Stem Cells and Regenerative Medicine, Birth Defects Research Centre, University College London Institute of Child Health, London WC1N 1EH, United Kingdom.
8 Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
9 Department of Pediatric Surgery, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands.
10 Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
11 Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands; j.m.miano@rochester.edu r.hofstra@erasmusmc.nl.
12 Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; j.m.miano@rochester.edu r.hofstra@erasmusmc.nl.

PMID: 28292896 DOI: 10.1073/pnas.1620507114

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.

Keywords

CRISPR-Cas9; Leiomodin; genetics; myopathy; smooth muscle.

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