Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype

Shinji Ito, Toshihide Iwashita, Naoya Asai, Hideki Murakami, Yosuke Iwata, Gen Sobue, Masahide Takahashi

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We investigated the transforming activity of the ret proto-oncogene with 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 these cysteine mutations, codon 634 mutations are known to be correlated with the development of MEN 2A, whereas codon 609, 618, or 620 mutations were detected in two-thirds of FMTCs and in several cases of Hirschsprung's disease. Analysis of a total of 18 mutant genes revealed that codon 634 mutations have the highest transforming activity. The activity 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 that of ret with a codon 634 mutation, respectively. In addition, different 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 mutations might impair transport of Ret to the plasma membrane, as observed for several Hirschsprung mutations affecting the Ret extracellular domain. These results thus suggest that mutations in cysteine 609, 611, 618, or 620 may have the potential to develop Hirschsprung's disease in addition to MEN 2A and FMTC.

Original languageEnglish
Pages (from-to)2870-2872
Number of pages3
JournalCancer Research
Issue number14
Publication statusPublished - 15-07-1997


All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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