{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T13:19:43Z","timestamp":1775654383019,"version":"3.50.1"},"reference-count":31,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2012,7,10]],"date-time":"2012-07-10T00:00:00Z","timestamp":1341878400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical Endocrinology"],"published-print":{"date-parts":[[2012,8]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>s play key roles in intrauterine and postnatal growth through the <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">I<\/jats:styled-content> receptor (<jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">IR<\/jats:styled-content>). We identified a family bearing a new heterozygous missense mutation at the <jats:styled-content style=\"fixed-case\">L<\/jats:styled-content>2 domain of <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">IR<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">R<\/jats:styled-content>431<jats:styled-content style=\"fixed-case\">L<\/jats:styled-content>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>We analysed the nucleotide sequences of the <jats:styled-content style=\"fixed-case\"><jats:italic>IGF1R<\/jats:italic><\/jats:styled-content> gene of the family. We prepared <jats:styled-content style=\"fixed-case\">R<\/jats:styled-content><jats:sup>\u2212<\/jats:sup> cells (fibroblasts with targeted disruption of the <jats:styled-content style=\"fixed-case\"><jats:italic>IGF\u2010IR<\/jats:italic><\/jats:styled-content> gene) expressing wild\u2010type or <jats:styled-content style=\"fixed-case\">R<\/jats:styled-content>431<jats:styled-content style=\"fixed-case\">L IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">IR<\/jats:styled-content> and performed functional analyses by evaluating <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">I<\/jats:styled-content> binding, <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">I<\/jats:styled-content>\u2010stimulated <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> synthesis, tyrosine phosphorylation of <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">IR<\/jats:styled-content> and its substrates, and internalization by measuring [<jats:sup>125<\/jats:sup><jats:styled-content style=\"fixed-case\"><jats:roman>I<\/jats:roman><\/jats:styled-content>]<jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">I<\/jats:styled-content> internalization. We also performed confocal microscopy analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified a family bearing a new heterozygous missense mutation at the <jats:styled-content style=\"fixed-case\">L<\/jats:styled-content>2 domain of <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">IR<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">R<\/jats:styled-content>431<jats:styled-content style=\"fixed-case\">L<\/jats:styled-content>) through an 8\u2010year\u2010old girl and her mother, both born with intrauterine growth retardation. In experiments conducted using cells homozygously transfected with the <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">IR R<\/jats:styled-content>431<jats:styled-content style=\"fixed-case\">L<\/jats:styled-content> mutation; (i) <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">I<\/jats:styled-content> binding was not affected; (ii) <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> synthesis induced by <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">I<\/jats:styled-content> was decreased; (iii) <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">IR<\/jats:styled-content> internalization stimulated by <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">I<\/jats:styled-content> was decreased and (iv) <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">I<\/jats:styled-content>\u2010stimulated tyrosine phosphorylation was reduced <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">IR<\/jats:styled-content> by low concentrations of <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">I<\/jats:styled-content> and on insulin receptor substrate (<jats:styled-content style=\"fixed-case\">IRS<\/jats:styled-content>)\u20101 and <jats:styled-content style=\"fixed-case\">IRS<\/jats:styled-content>\u20102.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>A missense mutation (<jats:styled-content style=\"fixed-case\">R<\/jats:styled-content>431<jats:styled-content style=\"fixed-case\">L<\/jats:styled-content>) leads to the inhibition of cell proliferation, attenuation of <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content> signalling and decrease in internalization of <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">IR<\/jats:styled-content>. The results of this study suggest a novel link between a mutation at the <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">IR L<\/jats:styled-content>2 domain and intrauterine and postnatal growth retardation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.1365-2265.2012.04357.x","type":"journal-article","created":{"date-parts":[[2012,2,7]],"date-time":"2012-02-07T03:20:33Z","timestamp":1328584833000},"page":"246-254","source":"Crossref","is-referenced-by-count":26,"title":["Novel missense mutation in the <scp>IGF<\/scp>\u2010<scp>I<\/scp> receptor <scp>L<\/scp>2 domain results in intrauterine and postnatal growth retardation"],"prefix":"10.1111","volume":"77","author":[{"given":"Yuki","family":"Kawashima","sequence":"first","affiliation":[{"name":"Division of Pediatrics &amp; Perinatology Yonago Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsumi","family":"Higaki","sequence":"additional","affiliation":[{"name":"Division of Functional Genomics Research Center for Bioscience and Technology Tottori University Faculty of Medicine Yonago Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiaki","family":"Fukushima","sequence":"additional","affiliation":[{"name":"Departments of Animal Sciences and Applied Biological Chemistry The University of Tokyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fumihiko","family":"Hakuno","sequence":"additional","affiliation":[{"name":"Departments of Animal Sciences and Applied Biological Chemistry The University of Tokyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun\u2010ichi","family":"Nagaishi","sequence":"additional","affiliation":[{"name":"Division of Pediatrics &amp; Perinatology Yonago Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keiichi","family":"Hanaki","sequence":"additional","affiliation":[{"name":"Division of Pediatrics &amp; Perinatology Yonago Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eiji","family":"Nanba","sequence":"additional","affiliation":[{"name":"Division of Functional Genomics Research Center for Bioscience and Technology Tottori University Faculty of Medicine Yonago Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shin\u2010Ichiro","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Departments of Animal Sciences and Applied Biological Chemistry The University of Tokyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susumu","family":"Kanzaki","sequence":"additional","affiliation":[{"name":"Division of Pediatrics &amp; Perinatology Yonago Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2012,7,10]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1006\/excr.1999.4667"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3835(03)00159-9"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(05)80084-4"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(05)80085-6"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1210\/edrv.22.6.0452"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa010107"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-1947"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-2146"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-1597"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2006-2354"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-1433"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-2404"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2010-1789"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/PL00000744"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd917"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M102863200"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.48.31640"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2834824"},{"key":"e_1_2_8_20_1","doi-asserted-by":"crossref","first-page":"21285","DOI":"10.1016\/S0021-9258(17)45358-0","article-title":"Mutagenesis of lysine 460 in the human insulin receptor. 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