title: A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome.
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.
authors.affiliation: Molecular Diagnostic Laboratory and Division of Medical Genetics, CHU Sainte-Justine, Montreal, Quebec, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Gauthier
authors.affiliation: Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada.
authors.forename: Bouchra
authors.initials: B
authors.lastname: Ouled Amar Bencheikh
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Harrison
authors.affiliation: 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.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Baker
authors.affiliation: Molecular Diagnostic Laboratory and Division of Medical Genetics, CHU Sainte-Justine, Montreal, Quebec, Canada.
authors.forename: Françoise
authors.initials: F
authors.lastname: Couture
authors.affiliation: Molecular Diagnostic Laboratory and Division of Medical Genetics, CHU Sainte-Justine, Montreal, Quebec, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Thiffault
authors.affiliation: Neurophysiology Division, Hospital of Specialities, CHIS Ibn Sina, Rabat, Marocco.
authors.forename: Reda
authors.initials: R
authors.lastname: Ouazzani
authors.affiliation: 1] CHU Sainte-Justine Research Center, Montreal, Quebec, Canada [2] Department of Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Samuels
authors.affiliation: 1] Molecular Diagnostic Laboratory and Division of Medical Genetics, CHU Sainte-Justine, Montreal, Quebec, Canada [2] CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
authors.forename: Grant A
authors.initials: GA
authors.lastname: Mitchell
authors.affiliation: 1] Molecular Diagnostic Laboratory and Division of Medical Genetics, CHU Sainte-Justine, Montreal, Quebec, Canada [2] Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.affiliation: 1] Molecular Diagnostic Laboratory and Division of Medical Genetics, CHU Sainte-Justine, Montreal, Quebec, Canada [2] CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
authors.affiliation: Molecular Diagnostic Laboratory and Division of Medical Genetics, CHU Sainte-Justine, Montreal, Quebec, Canada.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Soucy
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D003106:Colon / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D003241:Consanguinity; D059472:Exome; D015870:Gene Expression; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D007413:Intestinal Mucosa / Q000378:metabolism; D007415:Intestinal Obstruction / Q000378:metabolism / Q000473:pathology; D007418:Intestinal Pseudo-Obstruction / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007422:Intestines / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics*; D011535:Prune Belly Syndrome / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017422:Sequence Analysis, DNA; D001743:Urinary Bladder / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology
chemical_list: C509903:MYH11 protein, human; D018995:Myosin Heavy Chains