Haplotype analysis of MEN 2 mutations

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