Familial form of Hirschsprung disease: Nucleotide sequence studies reveal point mutations in the RET proto-oncogene in two of six families but not in other candidate genes

Abstract

Hirschsprung disease (HSCR; McKusick 142623) or aganglionic megacolon is a frequent (1 in 5,000 live births) heritable disorder of the enteric nervous system. By haplotyping with a variety of microsatellite markers, by amplifying all 20 exons of the RET proto-oncogene and by applying a direct DNA sequencing protocol, we have analyzed the DNA from HSCR patients in 6 different families. In one family with a joint occurrence of HSCR and FMTC (follicular medullary thyroid carcinoma), we have identified a mutation in codon 609 in one out of 6 cysteine residues encoded in exon 10 of the RET gene. This C609R point mutation has not previously been reported to cause HSCR. In 2 of the HSCR patients described here from different families, we have found a mutation in exon 2 (R77C) and a silent mutation in exon 3 (Y204Y), respectively, in the extracellular part of the RET proto-oncogene. In introns 2 and 17 of the RET proto-oncogene in 2 families, we have detected single nucleotide exchanges that are probably polymorphisms with unknown, if any, relations to HSCR. The DNA sequences of 5 further genes (GDNF, GDNFRalpha, EDN3, EDNRB, and NTN), that may contribute to the development of HSCR, have not shown mutations in the patients analyzed so far. In 2 of the reported families with several affected children and one grandchild, sequence analyses revealed no mutations in the coding regions of any of the candidate genes analyzed.

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

“…Using PCR and direct sequencing, we screened all exons of the RET, EDNRB, EDN3, and GDNF genes, including intron/exon boundaries, for mutations and polymorphisms. The primers and PCR conditions for amplification of the RET and EDN3 genes have been described previously (6,12 ). For amplification of RET exon 21 and the EDNRB and GDNF genes, we generated new pairs of primers (Table 1).…”

“…HSCR has a complex genetic etiology, with many studies indicating the receptor tyrosine kinase gene (RET) as the major susceptibility gene for HSCR (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). 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).…”

“…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).…”

BRCA1 185delAG truncation protein, BRAt, amplifies caspase-mediated apoptosis in ovarian cells

“…BRCA1 deletions in exons 2, 3, 9, 10, 11, 14, 15, 16, 17, and 18 also produce truncation proteins within the same open reading frame as the wild-type BRCA1 transcript, yet they posses unique properties. For example, splice variants produced from the BRCA 1b exon appear only in placental tissue, and splice variants lacking exon 7 are found predominantly in lymphocytes (Xu et al 1995;Munnes et al 2000). Transcripts lacking exon 11 lose the ability to translocate to the nucleus and have been shown to cause increased radiation-induced apoptosis in both human fibroblasts and breast cancer carcinoma cell lines (Shao et al 1996;Orban and Olah 2003).…”

Ovarian tumors associated with multiple endocrine neoplasias and related syndromes (Carney complex, Peutz–Jeghers syndrome, von Hippel-Lindau disease, Cowden's disease)

“…In MEN 2B, the mutations are in the tyrosine kinase domain. Finally, mutations of RET and its ligand, glial-derived nerve growth factor (GDNF), have been found in approximately half of the 10% of familial cases of Hirschsprung disease and its variants (33,34) .…”