Gene Chips Give Clues to Hirschsprung Disease

The findings were published September 23, 2002, in the online edition of Nature Genetics.

The investigators, from Johns Hopkins University (Baltimore, MD, USA), studied a group of 43 Old Order Mennonite families. Hirschsprung disease occurs in Mennonite communities in about one out of 500 births, a rate roughly 10 times higher than in the general population.

Employing gene chip technology combined with sophisticated computer analysis, they found susceptibility loci at 10q11, 13q22 and 16q23; the gene at 13q22 is EDNRB, encoding a G protein–coupled receptor (GPCR) and the gene at 10q11 is RET, encoding a receptor tyrosine kinase (RTK). For the clinical disease to be manifested mutations had to be present in both EDNRB and RET.

Two mouse strains were developed, one with RET disrupted and the other with EDNRB disrupted. While neither parental line of mice had intestinal symptoms, breeding the two lines together produced offspring that exhibited conditions more similar to Hirschsprung than any previous attempt to model the disease.

"By tracking thousands of genetic variations passed to affected children by their unaffected parents, we discovered which markers were important in the disease and which ones were not,” explained first author Dr. Minerva Carrasquillo. Exactly how abnormal RET and EDNRB genes coordinate to cause Hirschsprung disease is not yet understood. The proteins encoded by the RET and EDNRB genes are involved in distinct pathways, although some evidence exists of indirect interaction between proteins related to RET and EDNRB. Both RET and EDNRB proteins are involved in connecting nerves to the digestive tract during embryo development.”



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