Loss-of-Function Variants in MYLK Cause Recessive Megacystis Microcolon Intestinal Hypoperistalsis Syndrome

Am J Hum Genet. 2017 Jul 6;101(1):123-129. doi: 10.1016/j.ajhg.2017.05.011.

Danny Halim ¹, Erwin Brosens ¹, Françoise Muller ², Michael F Wangler ³, Arthur L Beaudet ³, James R Lupski ⁴, Zeynep H Coban Akdemir ⁵, Michael Doukas ⁶, Hans J Stoop ⁶, Bianca M de Graaf ¹, Rutger W W Brouwer ⁷, Wilfred F J van Ijcken ⁷, Jean-François Oury ⁸, Jonathan Rosenblatt ⁸, Alan J Burns ⁹, Dick Tibboel ¹⁰, Robert M W Hofstra ¹¹, Maria M Alves ¹²

Affiliations

1 Department of Clinical Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
2 Biochimie Prenatale, Hôpital Universitaire Robert Debré, 75019 Paris, France.
3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Childen's Hospital, Houston, TX 77030, USA.
4 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Childen's Hospital, Houston, TX 77030, USA; Baylor-Hopkins Center for Mendelian Genomics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
5 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor-Hopkins Center for Mendelian Genomics, Baylor College of Medicine, Houston, TX 77030, USA.
6 Department of Pathology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
7 Erasmus Center for Biomics, Erasmus Medical Center, 3000 CA Rotterdam, the Netherlands.
8 Department of Obstetrics and Gynecology, Hôpital Universitaire Robert Debré, 75019 Paris, France.
9 Department of Clinical Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands; Stem Cells and Regenerative Medicine, Birth Defects Research Centre, UCL Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK.
10 Department of Pediatric Surgery, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
11 Department of Clinical Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands; Stem Cells and Regenerative Medicine, Birth Defects Research Centre, UCL Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK. Electronic address: [email protected].
12 Department of Clinical Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands. Electronic address: [email protected].

PMID: 28602422 DOI: 10.1016/j.ajhg.2017.05.011

Abstract

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^∗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.

Keywords

MMIHS; MYLK; bladder and intestinal obstruction; smooth muscle contractility.

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