HAPLOTYPE ANALYSIS OF MEN-2 MUTATIONS

Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome which affects thyroid C cells, and with variable frequ ency, the adrenal medulla, parathyroid and enteric autonomic ganglia. The syndrome is due to germline mutation in the receptor tyrosine kina se gene, RET. We have recently shown an unexpected correlation between one particular RET mutation, cys634-->arg, and the probability of par athyroid involvement in families with MEN 2A. Here we use haplotype an alysis in the families to show that this correlation is not explained by a single founder chromosome which carries both the cys634-->arg mut ation and a separate allele conferring susceptibility to parathyroid a bnormality, but is probably due to the cys634-->arg mutation itself. T he results also indicate that new mutations to MEN 2 are not infrequen t.