title: Truncating mutation in the nitric oxide synthase 1 gene is associated with infantile achalasia.
abstract: 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.
authors.affiliation: Pediatric Gastroenterology Unit, Department of Pediatrics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Electronic address: eyals@szmc.org.il.
authors.forename: Eyal
authors.initials: E
authors.lastname: Shteyer
authors.affiliation: Neuropediatric Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Simon
authors.initials: S
authors.lastname: Edvardson
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Wynia-Smith
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
authors.forename: Ciro Leonardo
authors.initials: CL
authors.lastname: Pierri
authors.affiliation: Pediatric Gastroenterology Unit, E Wolfson Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Tzili
authors.initials: T
authors.lastname: Zangen
authors.affiliation: Emergency Medicine Department of Pediatrics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Saar
authors.initials: S
authors.lastname: Hashavya
authors.affiliation: Neuropediatric Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Begin
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Barak
authors.initials: B
authors.lastname: Yaacov
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Cinamon
authors.affiliation: Department of Medical Imaging, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Benjamin Z
authors.initials: BZ
authors.lastname: Koplewitz
authors.affiliation: Department of Pediatric Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Amos
authors.initials: A
authors.lastname: Vromen
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Smith
mesh_terms: D004931:Esophageal Achalasia / Q000235:genetics*; D052138:Genes, Neoplasm / Q000235:genetics*; D006519:Hepatitis, Alcoholic / Q000276:immunology*; D006801:Humans; D016031:Liver Transplantation / Q000639:trends*; D052248:Nitric Oxide Synthase Type I / Q000235:genetics*; D065626:Non-alcoholic Fatty Liver Disease / Q000453:epidemiology*; D010190:Pancreatic Neoplasms / Q000235:genetics*
chemical_list: C496320:NOS1 protein, human; D052248:Nitric Oxide Synthase Type I
keywords: Esophageal Disorder; Human Genetics; Muscle Relaxation; Swallow