Hit By Two Hammers: Hirschsprung Disease

Mutations in at least twelve individual genes are associated with the congenital defect Hirschsprung Disease (HSCR), in which children are born lacking nerves that innervate the gastrointestinal tract.

As a result, the affected portion of intestine or bowel cannot undergo peristaltic movements and affected individuals are left with lasting complications including constipation, dehydration and poor nutrient absorption.

Investigator Paul Trainor, PhD, and Amanda Barlow, PhD, a former postdoctoral scientist in the lab, identified new genetic interactions associated with HSCR and showed how the migration of cells that form the gut nervous system is impeded when the combined doses of two candidate genes, known as Tcof1 and Pax3, are low. The cells that go awry in HSCR are a subset of neural crest cells, embryonic cells that spring from the developing brain and spinal cord in mice or humans and then travel long distances to form, among other things, bone and cartilage structures in the face, smooth muscle in the heart, and neurons of the peripheral nervous system, including those that innervate the gut.

Trainor has been interested in neural crest cells since he was a graduate student, often focusing on developmental defects caused by their malfunction. “Neural crest cells have to be born in the right place, migrate incredibly long distances, survive, multiply, and then differentiate into many different mature cell types,” says Trainor, who until recently was primarily interested in neural crest-related craniofacial anomalies. “In Hirschsprung Disease neural crest cells don’t make it to the end of the gastrointestinal tract, and we need to better understand why in the hope of eventually minimizing or preventing this from happening in newborn babies.”

Understanding the genetic basis of HSCR offers hope for better diagnostics and treatment for this and other developmental defects caused by the failure of neural crest cell development.

The study was published in the January 2013 issue of Human Molecular Genetics and a review of the etiology and pathogenesis of HSCR by Naomi Butler Tjaden (a predoctoral student in the Trainor lab) was published in the March 2013 issue of Translational Research.