Truncating mutation in the nitric oxide synthase 1 gene is associated with infantile achalasia

Gastroenterology. 2015 Mar;148(3):533-536.e4. doi: 10.1053/j.gastro.2014.11.044. Epub 2014 Dec 3.


Nitric oxide is thought to have a role in the pathogenesis of achalasia. We performed a genetic analysis of 2 siblings with infant-onset achalasia. Exome analysis revealed that they were homozygous for a premature stop codon in the gene encoding nitric oxide synthase 1. Kinetic analyses and molecular modeling showed that the truncated protein product has defects in folding, nitric oxide production, and binding of cofactors. Heller myotomy had no effect in these patients, but sildenafil therapy increased their ability to drink. The finding recapitulates the previously reported phenotype of nitric oxide synthase 1-deficient mice, which have achalasia. Nitric oxide signaling appears to be involved in the pathogenesis of achalasia in humans.

Keywords: Esophageal Disorder; Human Genetics; Muscle Relaxation; Swallow.

Publication types

  • Comment

MeSH terms

  • Esophageal Achalasia / genetics*
  • Genes, Neoplasm / genetics*
  • Hepatitis, Alcoholic / immunology*
  • Humans
  • Liver Transplantation / trends*
  • Nitric Oxide Synthase Type I / genetics*
  • Non-alcoholic Fatty Liver Disease / epidemiology*
  • Pancreatic Neoplasms / genetics*


  • NOS1 protein, human
  • Nitric Oxide Synthase Type I