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.

Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice

“…Further, smooth muscle-specific knockout of myosin light chain kinase results in early postnatal demise due to similar phenotypes observed in the Lmod1 and Myh11 knockouts (41). Although human mutations in the latter have not yet been documented, there is a report of a consanguineous family with a nonsense mutation in MYH11 associated with MMIHS (10). Inactivation of SmoothelinA, encoding a visceral smooth muscle restricted actin-binding protein (42), results in impaired intestinal contractility and 50% mortality in homozygous mutants by postnatal day 20 (43); no human mutations have yet been reported for SmoothelinA.…”

“…Previous studies have documented spontaneous and autosomal dominant mutations in ACTG2 or a recessive mutation in MYH11 in patients diagnosed with MMIHS, a rare congenital disease in visceral smooth muscle of the intestine and urinary bladder (8,10). However, there is emerging evidence for considerable heterogeneity in the disease, and additional recessive mutations are likely (4).…”

“…Heterozygous mutations in ACTG2 are also observed in patients with autosomal dominant MMIHS (6,8), but there is emerging evidence for a recessive mode of inheritance. For example, a homozygous loss-of-function variant in the myosin heavy chain 11 (MYH11) gene, which is another highly specific contractile gene for smooth muscle lineages (9), was reported in a patient with MMIHS from a consanguineous (i.e., genetically related) couple (10). To date, no other smooth muscle-restricted contractile genes have been linked to MMIHS.…”

Variants of the ACTG2 gene correlate with degree of severity and presence of megacystis in chronic intestinal pseudo-obstruction

“…Since a homozygous nonsense variant in the MYH11 gene, coding for the smooth muscle myosin heavy chain, has been identified in one MMIHS patient from consanguineous parents, 15 we searched for variants of this gene in our 3 familial cases without finding any variant (not shown).…”

Exome sequencing identifies recessive CDK5RAP2 variants in patients with isolated agenesis of corpus callosum

“…8 Variants were validated using Sanger sequencing (Supplementary Table S1) and Mutation Surveyor (v.3.23, Softgenetics, LLC, State College, PA, USA). Variants and phenotypes have been submitted into the public database ClinVar (submission ID SCV000222772; http://www.ncbi.nlm.nih.gov/clinvar/).…”