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

著者: Danny Halim, Michael P. Wilson, Daniel Oliver, Erwin Brosens, Joke B. G. M. Verheij, Han Yu, Vivek Nanda, Qing Lyu, Michael Doukas, Hans Stoop, Rutger W. W. Brouwer, Wilfred F. J. van IJcken, Orazio J. Slivano, Alan J. Burns, Christine K. Christie, Karen L. de Mesy Bentley, Alice S. Brooks, Dick Tibboel, Suowen Xu, Zheng Gen Jin, Tono Djuwantono, Wei Yan, Maria M. Alves, Robert M.W. Hofstra, Joseph M. Miano - Proceedings of the National Academy of Sciences, PNAS 2017 被引用: 127

Significance Rare recessive monogenic diseases are often found in isolated populations. In one such population, we identified a child carrying a homozygous nonsense mutation in an understudied smooth muscle-restricted gene called Leiomodin1 ( LMOD1 ). Heterozygous parents showed no disease; however, the child died shortly after birth from a rare condition known as megacystis microcolon intestinal hypoperistalsis syndrome. A mouse model with a similar Lmod1 mutation, engineered with CRISPR-Cas9 genome editing, exhibited the same gastrointestinal and urinary bladder phenotypes as seen in the newborn child. Phenotyping revealed insights into the underlying cause of the disease. Results demonstrate the conserved function of LMOD1 in human and mice and the importance of this protein in the molecular regulation of contractility in visceral smooth muscle cells.