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

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

Author information

1
Pediatric Gastroenterology Unit, Department of Pediatrics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Electronic address: eyals@szmc.org.il.
2
Neuropediatric Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
3
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin.
4
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
5
Pediatric Gastroenterology Unit, E Wolfson Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
6
Emergency Medicine Department of Pediatrics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
7
Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
8
Department of Medical Imaging, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
9
Department of Pediatric Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

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.

KEYWORDS:

Esophageal Disorder; Human Genetics; Muscle Relaxation; Swallow

Comment on

  • Gastroenterology. 2015 Mar;148(3):459-61.
PMID:
25479138
DOI:
10.1053/j.gastro.2014.11.044
[Indexed for MEDLINE]

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