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. Epub 2014 Nov 19.

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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / metabolism
  • Abnormalities, Multiple / pathology
  • Base Sequence
  • Colon / abnormalities*
  • Colon / metabolism
  • Colon / pathology
  • Consanguinity
  • Exome
  • Gene Expression
  • Homozygote*
  • Humans
  • Infant, Newborn
  • Intestinal Mucosa / metabolism
  • Intestinal Obstruction / metabolism
  • Intestinal Obstruction / pathology
  • Intestinal Pseudo-Obstruction / complications
  • Intestinal Pseudo-Obstruction / genetics*
  • Intestinal Pseudo-Obstruction / metabolism
  • Intestinal Pseudo-Obstruction / pathology
  • Intestines / pathology
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Myosin Heavy Chains / genetics*
  • Prune Belly Syndrome / complications
  • Prune Belly Syndrome / genetics*
  • Prune Belly Syndrome / metabolism
  • Prune Belly Syndrome / pathology
  • Sequence Analysis, DNA
  • Urinary Bladder / abnormalities*
  • Urinary Bladder / metabolism
  • Urinary Bladder / pathology

Substances

  • MYH11 protein, human
  • Myosin Heavy Chains

Supplementary concepts

  • Megacystis microcolon intestinal hypoperistalsis syndrome
  • Microcolon