Human Molecular Genetics, Vol 5, 1577-1580, Copyright © 1996 by Oxford University Press
T Iwashita, H Murakami, N Asai and M Takahashi
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.
ARTICLES
Mechanism of ret dysfunction by Hirschsprung mutations affecting its extracellular domain
Department of Pathology, Nagoya University School of Medicine, Japan.
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