Altered regulation of smooth muscle myosin in esophageal atresia

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PROJECT SUMMARY Esophageal atresia (EA) is the most common congenital disorder of the esophagus with a world-wide incidence of about 1 in 3,500 live births. EA can occur as an isolated finding, or in combination with other developmental anomalies. Left untreated, EA is a fatal disorder because the atretic segment obstructs the esophagus. Fortunately, surgical correction of EA is possible in infancy. EA is thus curable in the vast majority of cases. Unfortunately most EA patients suffer from significant gastroesophageal reflux and dysphagia post- operatively as a result of impaired esophageal motility. The cause of EA is not known, however its frequent occurrence as part of complex developmental syndromes, and its higher incidence in monozygotic vs. dizygotic twins argues in favor of genetic factors. No single gene mutations have been conclusively shown to cause EA in humans. We have developed the first animal model of isolated EA occurring without other developmental anomalies by engineering a mutation in the smooth muscle myosin heavy chain gene (Myh11) that we have previously shown alters myosin regulation. In zebrafish, the identical mutation causes invasive expansion of the intestine. In mice the predominant phenotype is EA, although invasive-like intestinal lesions are detected. The mutation disrupts smooth muscle contractility as a result of altered myosin regulation. This suggests that genetic variants in MYH11 and other smooth muscle regulatory genes could cause both EA and account for post-surgical esophageal motility disorders. The goal of this proposal is to explore both the mechanism of EA in the Myh11 mouse model and to identify novel genetic variants in EA patients using exome sequencing.