caa a22 4500 397573928 CHVBK 20180308164849.0 cr unu---uuuuu 161202e199610 xx s 000 0 eng 10.1093/hmg/5.10.1577 doi (NATIONALLICENCE)oxford-10.1093/hmg/5.10.1577 Mechanism of Ret Dysfunction by Hirschsprung Mutations Affecting Its Extracellular Domain [Elektronische Daten] [Toshihide Iwashita, Hideki Murakami, Naoya Asai, Masahide 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. © 1996 Oxford University Press Iwashita Toshihide Department of Pathology, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466, Japan aut Murakami Hideki Department of Pathology, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466, Japan aut Asai Naoya Department of Pathology, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466, Japan aut Takahashi Masahide Department of Pathology, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466, Japan aut Human Molecular Genetics Oxford University Press 5/10(1996-10), 1577-1580 0964-6906 5:10<1577 1996 5 hmg https://doi.org/10.1093/hmg/5.10.1577 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1093/hmg/5.10.1577 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Iwashita Toshihide Department of Pathology, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466, Japan aut NATIONALLICENCE 700 1- Murakami Hideki Department of Pathology, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466, Japan aut NATIONALLICENCE 700 1- Asai Naoya Department of Pathology, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466, Japan aut NATIONALLICENCE 700 1- Takahashi Masahide Department of Pathology, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466, Japan aut NATIONALLICENCE 773 0- Human Molecular Genetics Oxford University Press 5/10(1996-10), 1577-1580 0964-6906 5:10<1577 1996 5 hmg Metadata rights reserved CC BY-NC-4.0 http://creativecommons.org/licenses/by-nc/4.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-oxford