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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Acknowledgements
JLM is a National Scientist of the Fonds de Recherche du Québec-Santé (FRQS), MES is supported by the CHU Ste-Justine Research Centre and also Genome Canada and IT received a scholarship from the RMGA (Réseau de médecine génétique appliquée du FRQS). We thank the members of the RMGA bioinformatic team (Alexandre Dionne-Laporte, Dan Spiegelman, Edouard Henrion and Ousmane Diallo) for the bioinformatic analysis of the exome-sequencing data. This work was supported by March of Dimes (grant no. 12-FY10–236 to JLM).
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Gauthier, J., Ouled Amar Bencheikh, B., Hamdan, F. et al. A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome. Eur J Hum Genet 23, 1266–1268 (2015). https://doi.org/10.1038/ejhg.2014.256
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DOI: https://doi.org/10.1038/ejhg.2014.256
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