A Heterozygous Frameshift Mutation in the Endothelin-3 (EDN-3) Gene in Isolated Hirschsprung's Disease

Abstract

Hirschsprung's disease, affecting one in 5000 live newborns, is the most common cause of neonatal intestinal obstruction. The obstruction or, later in life, constipation arises from the lack of enteric ganglia in the hindgut, thus resulting in poor coordination of peristalsis. Mutations in Hirschsprung patients have so far been reported in five genes associated in two different receptor-ligand systems, RET-GDNF/NTN and EDNRB-EDN-3, and an additional gene with yet unknown precise function, SOX10. We report the results of single-stranded conformation polymorphism screening of the endothelin-3 gene in a Swedish population-based material of 66 sporadic and nine familial Hirschsprung's disease cases. We have found a novel heterozygous mutation in exon 2, c.262insG, in a patient with sporadic short segment Hirschsprung's disease without any Waardenburg features. This frameshift results in a premature stop two codons further on. Because this stop is introduced 5' of the biologically active protein, this mutation can hence be predicted to result in haplo-insufficiency.

Update on endothelins - biology and clinical implications

“…A heterozygous frameshift mutation resulting in a premature stop codon in the ET3 gene has been identified in a patient with sporadic short segment Hirschsprung disease [37]. The proposed mechanism for the ET-3/ETB receptor interactions involves regulation of mammalian neural crest development, specifically the vagal neural crest enteric ganglion neurons and the truncal neural crest-derived epidermal melanocytes.…”

A heterozygous endothelin 3 mutation in Waardenburg-Hirschsprung disease: is there a dosage effect of EDN3/EDNRB gene mutations on neurocristopathy phenotypes?

“…Mutations in the RET ligand GDNF (glial cell line derived neurotrophic factor) may also affect the phenotype 5-7. A few patients with HSCR were found to have heterozygous mutations in the genes encoding the endothelin B receptor ( EDNRB )8-10 or its ligand endothelin 3 ( EDN3 ) 1112 …”

“…As in most other cases described, penetrance was incomplete. Two of the three heterozygous EDN3 mutations so far identified in isolated HSCR were inherited from an asymptomatic mother,12 while one was inherited from a mother with a mild intestinal phenotype 11. Incomplete penetrance and phenotypic variability are frequent in neurocristopathies, particularly in HSCR.…”

Clinical relationship between EDN-3 gene, EDNRB gene and Hirschsprung’s disease

“…The importance of the EDN-3-EDNRB interaction in promoting the normal development of neural crest cells has been clearly demonstrated. Human mutations in the EDN-3 gene have been reported recently: heterozygous missense mutations in two cases of sporadic HD [17][18][19] . However, there are fewer reports about mutations of EDNRB gene and EDN-3 gene in HD in Chinese population.…”