BIOLOGICAL PROPERTIES OF RET WITH CYSTEINE MUTATIONS CORRELATE WITH MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A, FAMILIAL MEDULLARY-THYROID CARCINOMA, AND HIRSCHSPRUNGS-DISEASE PHENOTYPE

We investigated the transforming activity of the ret proto-oncogene wi th a mutation in cysteine 609, 611, 618, 620, 630, or 634 detected in patients with multiple endocrine neoplasia type 2A (MEN 2A), familial medullary thyroid carcinoma (FMTC), or Hirschsprung's disease. Of thes e cysteine mutations, codon 634 mutations are known to be correlated w ith the development of MEN 2A, whereas codon 609, 618, or 620 mutation s were detected in two-thirds of FMTCs and in several cases of Hirschs prung's disease. Analysis of a total of 18 mutant genes revealed that codon 634 mutations have the highest transforming activity, The activi ty of ret with a codon 609, 611, 618, or 620 mutation and with a codon 630 mutation was approximately 3- to 5-fold and 2-fold lower than tha t of ret with a codon 634 mutation, respectively, In addition, differe nt amino acid substitutions for the same cysteine displayed comparable transforming activity. The expression of the cell surface form of Ret with codon 609, 611, 618, or 620 mutation was very low compared with that of Ret with codon 634 mutation, indicating that the former four m utations might impair transport of Ret to the plasma membrane, as obse rved for several Hirschsprung mutations affecting the Ret extracellula r domain. These results thus suggest that mutations in cysteine 609, 6 11, 618, or 620 may have the potential to develop Hirschsprung's disea se in addition to MEN 2A and FMTC.