Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease

Abstract

Hirschsprung disease (HSCR, aganglionic megacolon) is a frequent congenital malformation regarded as a multigenic neurocristopathy. Two susceptibility genes have been recently identified in HSCR, namely the RET proto-oncogene and the endothelin B receptor (EDNRB) gene. Hitherto however, homozygosity for EDNRB mutations accounted for the HSCR-Waardenburg syndrome (WS) association. Here, we report heterozygous EDNRB missense mutations (G57S, R319W and P383L) in isolated HSCR. These data might suggest that EDNRB mutations could be dosage sensitive: heterozygosity would predispose to isolated HSCR with incomplete penetrance, while homozygosity would result in more complex neurocristopathies associating HSCR and WS features. In addition, the present data give further support to the role of the endothelin-signalling pathway in the development of neural crest-derived enteric neurons.

Highly Recurrent RET Mutations and Novel Mutations in Genes of the Receptor Tyrosine Kinase and Endothelin Receptor B Pathways in Chinese Patients with Sporadic Hirschsprung Disease

“…The result would be a shorter protein lacking highly conserved residues of the seventh transmembrane domain of the receptor. A missense mutation affecting the same codon (P383L) is known to be responsible for the HSCR phenotype (17 ). Functional analysis of P383L demonstrated that ligand-binding sites were reduced and that signal transduction was impaired (43 ).…”

“…The nonsynonymous change V185M is new and was found in two mutation-free SSA patients (maternal inheritance) and in one control. 5ЈUT Ϫ26GϾA, initially reported as a mutation (14,17 ), has recently been reported as a SNP (rs2070591) after a comprehensive study of SNPs in a Japanese population (44 ). In our study, 5ЈUT Ϫ26GϾA was found in one control and two SSA patients, one of whom (patient 61) also harbored IVS4 Ϫ14TϾC (both inherited from the father).…”

“…Mutations in the RET gene account for up to 50% of familial cases and 7%-35% of sporadic cases (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Other HSCR genes identified to date mainly code for protein members of the RET and endothelin receptor B (EDNRB) signaling pathways, which are interrelated and involved in the development of enteric ganglia from specific lineage of neural crest cells (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Mutations in these genes account for a small proportion of HSCR patients (7%) and have reduced penetrance and various effects on the length of the aganglionosis (1,2 ), suggesting that modifier genes influence the penetrance and severity of the phenotype (28,29 ).…”

The Regulation of Normal Melanocyte Proliferation

“…The classical example is piebaldism, a condition characterized by white patches devoid of melanocytes due to mutations that inactivate the KIT receptor (70). Likewise, mutations in the endothelin-B receptor (EDNRB) and endothelin-3 have been identified in patients with Hirschsprung disease (HSCR) and Waardenburg syndrome (WS), disorders involving neural crest-derived cells associated with piebaldism (71)(72)(73)(74).…”

EDNRB/EDN3 and Hirschsprung Disease Type II

“…Heterozygous EDNRB deletions have also been identified in patients with HSCR (45). A subsequent finding that a HSCR patient with retinoblastoma, harboring a large cytogenetic deletion spanning 13q14 to 13q22, in which EDNRB is not deleted, suggests that proximal genomic rearrangements may disrupt upstream regulatory elements and consequently inactivate EDNRB (46).…”