Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome.

[megacystis-microcolon-intestinal hypoperistalsis syndrome]

Megacystis-microcolon -intestinal hypoperistalsis syndrome (MMIHS ) is a rare disorder of enteric smooth muscle function affecting the intestine and bladder . Patients with this severe phenotype are dependent on total parenteral nutrition and urinary catheterization . The cause of this syndrome has remained a mystery since Berdon 's initial description in 1976 . No genes have been clearly linked to MMIHS . We used whole-exome sequencing for gene discovery followed by targeted Sanger sequencing in a cohort of patients with MMIHS and intestinal pseudo-obstruction . We identified heterozygous ACTG 2 missense variants in 15 unrelated subjects , ten being apparent de novo mutations . Ten unique variants were detected , of which six affected CpG dinucleotides and resulted in missense mutations at arginine residues , perhaps related to biased usage of CpG containing codons within actin genes . We also found some of the same heterozygous mutations that we observed as apparent de novo mutations in MMIHS segregating in families with intestinal pseudo-obstruction , suggesting that ACTG 2 is responsible for a spectrum of smooth muscle disease . ACTG 2 encodes Î³ 2 enteric actin and is the first gene to be clearly associated with MMIHS , suggesting an important role for contractile proteins in enteric smooth muscle disease .

Diseases
Validation

Diseases presenting "severe phenotype" symptom

22q11.2 deletion syndrome

achondroplasia

adrenomyeloneuropathy

alexander disease

alpha-thalassemia

aniridia

aromatase deficiency

canavan disease

cystinuria

dentin dysplasia

dentinogenesis imperfecta

harlequin ichthyosis

hirschsprung disease

hydrocephalus with stenosis of the aqueduct of sylvius

krabbe disease

lamellar ichthyosis

megacystis-microcolon-intestinal hypoperistalsis syndrome

neonatal adrenoleukodystrophy

oligodontia

triple a syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

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