HGM2002 Poster Abstracts: 8. Disease Mechanisms
POSTER NO: 406
A potential hot-spot for mutations in the RET proto-oncogene for Hirschsprung's disease
1B.L.S. Chen, 1M.M. Garcia-Barcelo, 1V.C.H. Lui, 2M.H. Sham, 1P.K.H. Tam
Among the known candidate genes implicated in Hirschsprung's disease (HSCR), the RET proto-oncogene remains the most important, accounting for 5-20% of sporadic cases and up to 40-50% of familial cases. Mutations are thought to be scattered along the whole length of the gene with no predominant susceptible regions, however, these findings were from collective series of diverse ethnic origins. In this study, we screened HSCR patients of a single race from a geographically confined population for novel mutations in the RET gene. Genomic DNA was extracted from peripheral blood samples of 92 HSCR patients (sporadic : familial = 87 : 5; short : long : total = 79 : 7 : 6) and 100 controls. PCR amplification followed by direct sequencing were performed on exon 3 of RET. Mutations found were confirmed by separate amplification analyses. Parents of patients with mutations were also screened. Three new heterozygous substitutions were found in the patient group but there was none in the controls. Seven patients carry a missense mutation G341A (R114H) (5 cases: inherited from unaffected parents, 2 cases: parents not available). One patient carried a de novo silent mutation C360T (T120T). Another patient had a de novo missense mutation T434G (V145G). Unlike MEN and MTC, RET mutations in HSCR are known to spread across all 21 exons. In this study, three novel mutations were identified in 9 of 92 (9.8%) patients, suggesting that exon 3 may be a high-risk, mutation-prone region in our ethnic population. Effects of these mutations on the protein are not clear. However, mutations in the extracellular domain may affect the folding or ligand-binding ability of RET. In addition, the occurrence of G341A (R114H) in unaffected parents reaffirms the nature of incomplete penetrance in HSCR.
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