Truncating mutation in the nitric oxide synthase 1 gene is associated with infantile achalasia. Gastroenterology 2015 Mar;148(3):533-536.e4
Date
12/06/2014Pubmed ID
25479138DOI
10.1053/j.gastro.2014.11.044Scopus ID
2-s2.0-84924061735 (requires institutional sign-in at Scopus site) 37 CitationsAbstract
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.
Author List
Shteyer E, Edvardson S, Wynia-Smith SL, Pierri CL, Zangen T, Hashavya S, Begin M, Yaacov B, Cinamon Y, Koplewitz BZ, Vromen A, Elpeleg O, Smith BCAuthors
Brian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of WisconsinSarah L. Wynia Smith Research Scientist II in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Esophageal AchalasiaGenes, Neoplasm
Hepatitis, Alcoholic
Humans
Liver Transplantation
Nitric Oxide Synthase Type I
Non-alcoholic Fatty Liver Disease
Pancreatic Neoplasms
