Novel RET Mutation Produces a Truncated RET Receptor Lacking the Intracellular Signaling Domain in a 3-Generation Family with Hirschsprung Disease

摘要

The RET gene encodes a transmembrane receptor tyrosine kinase, RET (1)(2), which is produced by enteric nervous system progenitors and functions, together with glial cell-line–derived neurotrophic factor (GDNF) family receptors, as the receptor for GDNF family ligands (3). Ligand binding induces RET dimerization, autophosphorylation of the tyrosine kinase (TK) domains, and intracellular signaling (3). RET mutations cause enteric nervous system anomalies in patients with Hirschsprung disease (HSCR), which is characterized by a deficiency of ganglion cells (aganglionosis) in the intramural plexuses of the colon (4)(5)(6).It is not always easy to offer biological evidence of alteration of the RET function for a large number of RET mutations in HSCR patients. Generally, mutations affecting the extracellular domain of RET could cause RET haploinsufficiency (7)(8) and/or interference of normal RET, causing RET signaling deficiency in a dominant fashion (9). Mutations affecting the intracellular domain of RET lead to interference of normal RET, causing RET functional deficiency in a dominant fashion (8)(10)(11)(12). The biological consequences of truncating mutations of RET is relatively little studied. In this study, we identified a novel truncating mutation of the RET gene and provided evidence indicating that the mutation could cause RET signaling deficiency in a dominant fashion and RET haploinsufficiency …