부산대학교 도서관

To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1016/j.ajhg.2017.05.011 Byline: Danny Halim (1), Erwin Brosens (1), Francoise Muller (2), Michael F. Wangler (3,4,5), Arthur L. Beaudet (3,4,5), James R. Lupski (3,4,5,6,7), Zeynep H. Coban Akdemir (3,6), Michael Doukas (8), Hans J. Stoop (8), Bianca M. de Graaf (1), Rutger W.W. Brouwer (9), Wilfred F.J. van Ijcken (9), Jean-Francois Oury (10), Jonathan Rosenblatt (10), Alan J. Burns (1,11), Dick Tibboel (12), Robert M.W. Hofstra [r.hofstra@erasmusmc.nl] (1,11,13,*), Maria M. Alves [m.alves@erasmusmc.nl] (1,13,**) Keywords MMIHS; MYLK; smooth muscle contractility; bladder and intestinal obstruction Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a congenital disorder characterized by loss of smooth muscle contraction in the bladder and intestine. To date, three genes are known to be involved in MMIHS pathogenesis: ACTG2, MYH11, and LMOD1. However, for approximately 10% of affected individuals, the genetic cause of the disease is unknown, suggesting that other loci are most likely involved. Here, we report on three MMIHS-affected subjects from two consanguineous families with no variants in the known MMIHS-associated genes. By performing homozygosity mapping and whole-exome sequencing, we found homozygous variants in myosin light chain kinase (MYLK) in both families. We identified a 7 bp duplication (c.3838_3844dupGAAAGCG [p.Glu1282_Glyfs.sup.*51]) in one family and a putative splice-site variant (c.3985+5C>A) in the other. Expression studies and splicing assays indicated that both variants affect normal MYLK expression. Because MYLK encodes an important kinase required for myosin activation and subsequent interaction with actin filaments, it is likely that in its absence, contraction of smooth muscle cells is impaired. The existence of a conditional-Mylk-knockout mouse model with severe gut dysmotility and abnormal function of the bladder supports the involvement of this gene in MMIHS pathogenesis. In aggregate, our findings implicate MYLK as a gene involved in the recessive form of MMIHS, confirming that this disease of the visceral organs is heterogeneous with a myopathic origin. Author Affiliation: (1) Department of Clinical Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands (2) Biochimie Prenatale, Hopital Universitaire Robert Debre, 75019 Paris, France (3) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA (4) Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA (5) Texas Childen's Hospital, Houston, TX 77030, USA (6) Baylor-Hopkins Center for Mendelian Genomics, Baylor College of Medicine, Houston, TX 77030, USA (7) Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA (8) Department of Pathology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands (9) Erasmus Center for Biomics, Erasmus Medical Center, 3000 CA Rotterdam, the Netherlands (10) Department of Obstetrics and Gynecology, Hopital Universitaire Robert Debre, 75019 Paris, France (11) Stem Cells and Regenerative Medicine, Birth Defects Research Centre, UCL Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK (12) Department of Pediatric Surgery, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands * Corresponding author Article History: Received 10 April 2017; Accepted 11 May 2017 (miscellaneous) Published: June 8, 2017 (footnote)13 These authors contributed equally to this work