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A leucine-to-proline mutation in the insulin receptor in a family with insulin resistance.

1989; Springer Nature; Volume: 8; Issue: 9 Linguagem: Inglês

10.1002/j.1460-2075.1989.tb08387.x

1460-2075

M. P. Klinkhamer, Nicole A. Groen, Gerard C. van der Zon, Dick Lindhout, L. A. Sandkuyl, H. M. J. Krans, W. Möller, J. A. Maassen,

Protein Kinase Regulation and GTPase Signaling

Research Article1 September 1989free access A leucine-to-proline mutation in the insulin receptor in a family with insulin resistance. M.P. Klinkhamer M.P. Klinkhamer Department of Medical Biochemistry, Sylvius Laboratory, Leiden, The Netherlands. Search for more papers by this author N.A. Groen N.A. Groen Department of Medical Biochemistry, Sylvius Laboratory, Leiden, The Netherlands. Search for more papers by this author G.C. van der Zon G.C. van der Zon Department of Medical Biochemistry, Sylvius Laboratory, Leiden, The Netherlands. Search for more papers by this author D. Lindhout D. Lindhout Department of Medical Biochemistry, Sylvius Laboratory, Leiden, The Netherlands. Search for more papers by this author L.A. Sandkuyl L.A. Sandkuyl Department of Medical Biochemistry, Sylvius Laboratory, Leiden, The Netherlands. Search for more papers by this author H.M. Krans H.M. Krans Department of Medical Biochemistry, Sylvius Laboratory, Leiden, The Netherlands. Search for more papers by this author W. Möller W. Möller Department of Medical Biochemistry, Sylvius Laboratory, Leiden, The Netherlands. Search for more papers by this author J.A. Maassen J.A. Maassen Department of Medical Biochemistry, Sylvius Laboratory, Leiden, The Netherlands. Search for more papers by this author M.P. Klinkhamer M.P. Klinkhamer Department of Medical Biochemistry, Sylvius Laboratory, Leiden, The Netherlands. Search for more papers by this author N.A. Groen N.A. Groen Department of Medical Biochemistry, Sylvius Laboratory, Leiden, The Netherlands. Search for more papers by this author G.C. van der Zon G.C. van der Zon Department of Medical Biochemistry, Sylvius Laboratory, Leiden, The Netherlands. Search for more papers by this author D. Lindhout D. Lindhout Department of Medical Biochemistry, Sylvius Laboratory, Leiden, The Netherlands. Search for more papers by this author L.A. Sandkuyl L.A. Sandkuyl Department of Medical Biochemistry, Sylvius Laboratory, Leiden, The Netherlands. Search for more papers by this author H.M. Krans H.M. Krans Department of Medical Biochemistry, Sylvius Laboratory, Leiden, The Netherlands. Search for more papers by this author W. Möller W. Möller Department of Medical Biochemistry, Sylvius Laboratory, Leiden, The Netherlands. Search for more papers by this author J.A. Maassen J.A. Maassen Department of Medical Biochemistry, Sylvius Laboratory, Leiden, The Netherlands. Search for more papers by this author Author Information M.P. Klinkhamer1, N.A. Groen1, G.C. Zon1, D. Lindhout1, L.A. Sandkuyl1, H.M. Krans1, W. Möller1 and J.A. Maassen1 1Department of Medical Biochemistry, Sylvius Laboratory, Leiden, The Netherlands. The EMBO Journal (1989)8:2503-2507https://doi.org/10.1002/j.1460-2075.1989.tb08387.x PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info We have determined the primary structure of a mutant insulin receptor of a leprechaun patient born from a consanguineous marriage. A characteristic feature of leprechaunism is an extreme resistance to insulin. In this patient the insulin resistance seems to result from an observed lack of insulin binding to intact cells. Solubilization of cells in non-ionic detergents leads to the appearance of insulin receptors which can bind insulin. However, the insulin-stimulated autophosphorylation of the receptor's beta subunit is markedly reduced. Cloning and sequencing of cDNA derived from insulin receptor mRNA of this patient revealed a leucine-to-proline mutation at position 233 in the alpha subunit. By means of DNA amplification we found that the patient is homozygous for this mutation and that the parents and two grandparents from the consanguineous line are heterozygous. The heterozygous individuals all show decreased insulin binding to cultured fibroblasts. In addition, they are mildly insulin resistant in vivo. These observations show a linkage between the leucine-to-proline mutation and the observed insulin resistance in this family. We therefore conclude that the mutation in the homozygous form is responsible for the extreme insulin resistance in the leprechaun patient. The mutation for the first time characterizes a region in the insulin receptor which seems to be involved in transmitting the insulin binding signal to the tyrosine kinase domain. Previous ArticleNext Article Volume 8Issue 91 September 1989In this issue RelatedDetailsLoading ...