Truncating Mutation in the Nitric Oxide Synthase 1 Gene Is Associated With Infantile Achalasia

被引：31

作者：

Shteyer, Eyal ^{[1
]}

Edvardson, Simon ^{[2
]}

Wynia-Smith, Sarah L. ^{[3
]}

Pierri, Ciro Leonardo ^{[4
]}

Zangen, Tzili ^{[5
]}

Hashavya, Saar ^{[6
]}

Begin, Michal ^{[2
]}

Yaacov, Barak ^{[7
]}

Cinamon, Yuval ^{[7
]}

Koplewitz, Benjamin Z. ^{[8
]}

Vromen, Amos ^{[9
]}

Elpeleg, Orly ^{[7
]}

Smith, Brian C. ^{[3
]}

机构：

[1] Hadassah Hebrew Univ Med Ctr, Dept Pediat, Pediat Gastroenterol Unit, Jerusalem, Israel

[2] Hadassah Hebrew Univ Med Ctr, Neuropediat Unit, Jerusalem, Israel

[3] Med Coll Wisconsin, Dept Biochem, Milwaukee, WI 53226 USA

[4] Univ Bari, Dept Biosci Biotechnol & Biopharmaceut, Bari, Italy

[5] Tel Aviv Univ, Sackler Sch Med, E Wolfson Med Ctr, Pediat Gastroenterol Unit, IL-69978 Tel Aviv, Israel

[6] Hadassah Hebrew Univ Med Ctr, Emergency Med Dept Pediat, Jerusalem, Israel

[7] Hadassah Hebrew Univ Med Ctr, Mon & Jacques Roboh Dept Genet Res, Jerusalem, Israel

[8] Hadassah Hebrew Univ Med Ctr, Dept Med Imaging, Jerusalem, Israel

[9] Hadassah Hebrew Univ Med Ctr, Dept Pediat Surg, Jerusalem, Israel

来源：

GASTROENTEROLOGY | 2015年 / 148卷 / 03期

关键词：

Human Genetics; Esophageal Disorder; Swallow; Muscle Relaxation; LOWER ESOPHAGEAL SPHINCTER; RAT ANOCOCCYGEUS MUSCLE; ESCHERICHIA-COLI; NEUROTRANSMITTER; RELAXATION; EXPRESSION; DISORDERS;

D O I：

10.1053/j.gastro.2014.11.044

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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.

引用

页码：533 / +

页数：8

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