Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease

Abstract

Hirschsprung disease (HSCR) is a common congenital malformation (1 in 5,000 live births) due to the absence of autonomic ganglia in the terminal hindgut, and resulting in intestinal obstruction in neonates. Recently, a dominant gene for familial HSCR has been mapped to chromosome sub-band 10q11.2 and the disease has been ascribed to mutations in a tyrosine kinase receptor gene mapping to this region, the RET proto-oncogene. Studying the 20 exons of the RET gene by a combination of denaturating gradient gel electrophoresis and single strand conformation polymorphism in a large series of HSCR patients (45 sporadic cases and 35 familial forms), we found mutations of the RET gene in 50% of familial HSCR, regardless of the length of the aganglionic segment. The mean penetrance of the mutant allele in familial HSCR was significantly higher in males (72%) than in females (51%). Most interestingly, mutations at the RET locus accounted for at least 1/3 of sporadic HSCR in our series. These mutations were scattered along the length of the gene. Finally, among the mutations identified in sporadic cases (16/45), seven proved to be de novo mutations suggesting that new mutations at the RET locus significantly contribute to sporadic HSCR. Taken together, the low penetrance of the mutant gene, the lack of genotype-phenotype correlation, the sex-dependent effect of RET mutations and the variable clinical expression of the disease support the existence of one or more modifier genes in familial HSCR.

Distinct biological properties of two RET isoforms activated by MEN 2A and MEN 2B mutations

“…Similarly, it is conceivable that each RET isoform might ful®ll di erent biological functions. The identi®cation in a family with HSCR of a RET missense mutation in exon 20 which codes for the carboxy terminus speci®c to the long isoform (Attie et al, 1995) strengthens the conception that RET isoforms could have intrinsic speci®city during development and contribute unequally to the pathogenesis of HSCR and MEN 2. In order to explore this hypothesis we focused our study on two RET isoforms, RET9 and RET51, which appear to be coexpressed in MTC and pheochromocytomas (Santoro et al, 1990;Myers et al, 1995).…”

Male and female differential reproductive rate could explain parental transmission asymmetry of mutation origin in Hirschsprung disease

“…A small subgroup of patients present a rare coding sequence mutation (CDS) of the RET gene with a high and sex-dependent penetrance. 1,2 The remaining group of patients have a risk allele for a noncoding polymorphism in an enhancer element of IVS1, rs2435357, with a low and sex-dependent penetrance [3][4][5][6] (found in 90% of the patient alleles versus 19.4% in the 1000 genomes project). The subgroup with RET CDS mutations represents B45% of familial cases and 7-20% of sporadic cases.…”

“…The subgroup with RET CDS mutations represents B45% of familial cases and 7-20% of sporadic cases. 4 Bolk et al 1 observed that the shared allele at RET among affected sib-pairs is more frequently inherited from the mother than the father. As families with and without RET CDS mutation were pooled, the question of whether parental transmission asymmetry is observed in both types of families remains unanswered.…”

Germline mutation of RET codon 883 in two cases of de novo MEN 2B

“…RET mutations are also found in some cases of dominantly inherited and sporadic Hirschsprung disease (Eng and Mulligan, 1997;Attie et al, 1995). Hirschsprung disease is the congenital lack of intestinal autonomic nerve plexuses.…”

“…Hirschsprung disease is the congenital lack of intestinal autonomic nerve plexuses. Missense mutations have been shown fully or partially to inactivate the RET kinase Carlomagno et al, 1996;Lorenzo et al, 1997), and many mutations lead to extreme truncations of the RET protein (Attie et al, 1995). In addition, papillary thyroid carcinoma (PTC) is associated with RET activation by somatic rearrangement to create constitutively active chimeric proteins (reviewed in Pierotti et al, 1996).…”