Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient

Abstract

Hirschsprung disease (HSCR), or congenital aganglionic megacolon, is the most common cause of congenital bowel obstruction with an incidence of 1 in 5000 live births. HSCR may be inherited as a single gene disorder with reduced penetrance or as a multigenic trait. HSCR mutations have been identified in the RET receptor tyrosine kinase, endothelin-B receptor (EDNRB) and its physiological ligand, endothelin 3 (EDN3). Although RET's ligand has remained elusive, it is expected to be an extracellular neurotrophic molecule expressed in the developing gut and kidney mesenchyme, based on the phenotypes of intestinal aganglionosis and renal agenesis observed in homozygous RET knockout (Ret -/-) mice. The glial cell line-derived neurotrophic factor (GDNF) is such a molecule. Recently, mice carrying two null alleles for Gdnf were shown to exhibit phenotypes remarkably similar to Ret-/- animals. We screened 106 unrelated HSCR patients for mutations in GDNF by direct sequencing. We identified one familial mutation in a HSCR patient with a known de novo RET mutation and malrotation of the gut. No haplotype sharing was evident in any of 36 HSCR kindreds typed for microsatellite markers surrounding GDNF on human chromosome 5p. Our data suggest that GDNF is a minor contributor to human HSCR susceptibility and that loss of its function in enteric neurogenesis may be compensated for by other neurotrophic factors or via other pathways. However, it may be that in rare instances, RET and GDNF mutations act in concert to produce an enteric phenotype.

Neurturin and Glial Cell Line-Derived Neurotrophic Factor Receptor-β (GDNFR-β), Novel Proteins Related to GDNF and GDNFR-α with Specific Cellular Patterns of Expression Suggesting Roles in the Developing and Adult Nervous System and in Peripheral Organs

“…These relationships may be analogous to those noted for the nerve growth factor families of trophic proteins and receptors, in which it is now realized that the neurotrophins exert a plethora of functions in the organism, including roles in the immune system, the endocrine system, and the reproductive system. Germ line as well as somatic mutations of members of the GDNF families of factors and receptors are known (Mulligan et al, 1993;Edery et al, 1994;Romeo et al, 1994;Angrist et al, 1996;Ivanchuk et al, 1996). Both loss of function and gain of function mutations of RET have been described.…”

Trisomy 7 mosaicism, maternal uniparental heterodisomy 7 and Hirschsprung's disease in a child with Silver–Russell syndrome

“…37 GRB10 was considered as a good candidate for HSCR susceptibility according to its early expression in the embryo 38,39 which is consistent with a role in enteric nervous system development. 37 However, no linkage or mutations of human GRB10 have been observed in a large panel of HSCR patients analysed.…”

A novel pathogenesis of megacolon in Ncx/Hox11L.1 deficient mice.

“…Hirschsprung's disease is characterized by the congenital absence of the enteric ganglia from the hindgut. Mutations in the c-RET gene (22,24), the glial cell line-derived neurotrophic factor gene (49,50), the endothelin-3 gene (51), and the endothelin-B receptor gene (23) were identified in Hirschsprung's disease. Neuronal intestinal dysplasia is a human congenital disorder which is characterized by a megacolon with a normal number of ganglia or hyperplasia of enteric neurons (52,53).…”