Mechanism of Ret dysfunction by Hirschsprung mutations affecting its extracellular domain

Toshihide Iwashita, Hideki Murakarni, Naoya Asai, Masahide Takahashi

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91 Citations (Scopus)


Hirschsprung disease (HSCR) is a congenital disorder associated with the absence of intrinsic ganglion cells in the distal gastrointestinal tract. Recently, many missense, nonsense and frameshift mutations of the ret proto-oncogene were found in familial and sporadic cases of HSCR. Consistent with the view that the HSCR phenotype is the result of inactivation of Ret, the missense mutations detected in the tyrosine kinase domain were demonstrated to result in a marked decrease of the kinase activity of Ret. However, the effects of missense mutations found in the extracellular domain remain unknown. We now report that five mutations in the extracellular domain examined inhibit transport of the Ret protein to the plasma membrane. As a consequence, they significantly decreased the transforming activity of Ret with multiple endocrine neoplasia (MEN) 2A mutation for which cell surface expression is required. Our results also demonstrated that long segment HSCR mutations more severely impair transport of Ret to the plasma membrane than a short segment HSCR mutation, suggesting that the level of its cell surface expression may correlate to the HSCR phenotype.

Original languageEnglish
Pages (from-to)1577-1580
Number of pages4
JournalHuman molecular genetics
Issue number10
Publication statusPublished - 10-1996
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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