Mutation of the RET ligand, neurturin, supports multigenic inheritance in Hirschsprung disease [published erratum appears in Hum Mol Genet 1998 Oct;7(11):1831]

Hirschsprung disease (HSCR) is a frequent neurocristopathy characterized bythe absence of submucosal and myenteric plexuses in a variable length ofthe gastrointestinal tract. Pedigrees and segregation analyses suggestedthe involvement of one or several dominant genes with low penetrance inHSCR. Considering that RET and glial cell line-derived neurotrophic factor(GDNF) mutations have been reported in the disease, we regarded the otherRET ligand, neurturin (NTN), as an attractive candidate gene, especially asit shares large homologies with GDNF. Here, we report on the finding of aheterozygous missense NTN mutation in a large non-consanguineous familyincluding four children affected with a severe aganglionosis phenotypeextending up to the small intestine. Interestingly, it appears that the NTNmutation reported here is not sufficient to cause HSCR, and this multiplexfamily also segregates a RET mutation. This cascade of independent andadditive genetic events fits well with the multigenic pattern ofinheritance expected in HSCR, and further support the role of RET ligandsin development of the enteric nervous system.