A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome

Eur J Hum Genet. 2015 Sep;23(9):1266-8. doi: 10.1038/ejhg.2014.256.

Julie Gauthier ¹, Bouchra Ouled Amar Bencheikh ², Fadi F Hamdan ³, Steven M Harrison ⁴, Linda A Baker ⁵, Françoise Couture ¹, Isabelle Thiffault ¹, Reda Ouazzani ⁶, Mark E Samuels ⁷, Grant A Mitchell ⁸, Guy A Rouleau ⁹, Jacques L Michaud ⁸, Jean-François Soucy ¹

Affiliations

1 Molecular Diagnostic Laboratory and Division of Medical Genetics, CHU Sainte-Justine, Montreal, Quebec, Canada.
2 Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada.
3 CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
4 Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
5 1] Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA [2] McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA [3] Children's Medical Center at Dallas, Dallas, TX, USA.
6 Neurophysiology Division, Hospital of Specialities, CHIS Ibn Sina, Rabat, Marocco.
7 1] CHU Sainte-Justine Research Center, Montreal, Quebec, Canada [2] Department of Medicine, University of Montreal, Montreal, Quebec, Canada.
8 1] Molecular Diagnostic Laboratory and Division of Medical Genetics, CHU Sainte-Justine, Montreal, Quebec, Canada [2] CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
9 1] Molecular Diagnostic Laboratory and Division of Medical Genetics, CHU Sainte-Justine, Montreal, Quebec, Canada [2] Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada.

PMID: 25407000 DOI: 10.1038/ejhg.2014.256

Abstract

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is characterized by marked dilatation of the bladder and microcolon and decreased intestinal peristalsis. Recent studies indicate that heterozygous variants in ACTG2, which codes for a smooth muscle actin, cause MMIHS. However, such variants do not explain MMIHS cases that show an autosomal recessive mode of inheritance. We performed exome Sequencing in a newborn with MMIHS and prune belly phenotype whose parents are consanguineous and identified a homozygous variant (c.3598A>T: p.Lys1200Ter) in MYH11, which codes for the smooth muscle Myosin heavy chain. Previous studies showed that loss of Myh11 function in mice causes a bladder and intestinal phenotype that is highly reminiscent of MMIHS. All together, these observations strongly suggest that loss-of-function variants in MYH11 cause MMIHS. The documentation of variants in ACTG2 and MYH11 thus points to the involvement of the contractile apparatus of the smooth muscle in MMIHS. Interestingly, dominant-negative variants in MYH11 have previously been shown to cause thoracic aortic aneurism and dilatation. Different mechanisms of MYH11 disruption may thus lead to distinct patterns of smooth muscle dysfunction.

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