Truncating Mutation in the Nitric Oxide Synthase 1 Gene is Associated with Infantile Achalasia.

Nitric oxide (NO) 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 (NOS1). Kinetic analyses and molecular modeling showed that the truncated protein product has defects in folding, NO 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 NOS1-deficient mice, which have achalasia. NO signaling appears to be involved in the pathogenesis of achalasia in humans.