{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T03:12:53Z","timestamp":1790305973464,"version":"4.1.0"},"reference-count":33,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2014,8,7]],"date-time":"2014-08-07T00:00:00Z","timestamp":1407369600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"FONCYT Argentina","award":["PICT 20080347"],"award-info":[{"award-number":["PICT 20080347"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical Endocrinology"],"published-print":{"date-parts":[[2015,5]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p><jats:italic><jats:styled-content style=\"fixed-case\">IGF1R<\/jats:styled-content><\/jats:italic> gene mutations have been associated with varying degrees of intrauterine and postnatal growth retardation, and microcephaly.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To identify and characterize <jats:italic><jats:styled-content style=\"fixed-case\">IGF1R<\/jats:styled-content><\/jats:italic> gene variations in a cohort of 28 Argentinean children suspected of having <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u20101 insensitivity, who were selected on the basis of the association of pre\/postnatal growth failure and microcephaly.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The coding sequence and flanking intronic regions of <jats:italic><jats:styled-content style=\"fixed-case\">IGF1R<\/jats:styled-content><\/jats:italic> gene were amplified and directly sequenced. Functional characterization was performed by two <jats:italic>in vitro<\/jats:italic> assays: 1) [Methyl\u2010<jats:sup>3<\/jats:sup>H] thymidine incorporation into <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> in fibroblast cell primary cultures from patients and controls treated with <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u20101 for 16\u201024\u00a0h. 2) PI3K\/Akt pathway was evaluated with phospho\u2010Akt (Ser473) <jats:styled-content style=\"fixed-case\">STAR ELISA<\/jats:styled-content> Kit (Millipore) in fibroblast cultures from patients and controls stimulated with <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u20101 for 10\u00a0min. Prepubertal clinical and <jats:styled-content style=\"fixed-case\">GH\u2010IGF<\/jats:styled-content>\u20101 axis evaluation was followed up.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified three novel heterozygous missense mutations in three unrelated patients, <jats:italic>de novo<\/jats:italic> p.Arg1256Ser, <jats:italic>de novo<\/jats:italic> p.Asn359Tyr and p.Tyr865Cys. In control cells, proliferation assay showed that <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u20101 significantly induced <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> synthesis at 20\u00a0h and Akt phosphorylation assay that it significantly stimulated phosphorylation after 10\u00a0min (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00\u00b705 by <jats:sc>anova<\/jats:sc> and Bonferroni Tests). However, no significant increase was observed in any of the three patient fibroblasts in both functional studies. <jats:styled-content style=\"fixed-case\">GH<\/jats:styled-content> therapy growth response in two patients was inconsistent.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These variations led to failure of the <jats:styled-content style=\"fixed-case\">IGF1R<\/jats:styled-content> function causing pre\u2010 and postnatal growth retardation and microcephaly. Microcephaly should be considered in the evaluation of <jats:styled-content style=\"fixed-case\">SGA<\/jats:styled-content> patients, because it seems to favour the frequency of detection of <jats:italic><jats:styled-content style=\"fixed-case\">IGF1R<\/jats:styled-content><\/jats:italic> mutations.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cen.12555","type":"journal-article","created":{"date-parts":[[2014,7,17]],"date-time":"2014-07-17T12:33:58Z","timestamp":1405600438000},"page":"704-711","source":"Crossref","is-referenced-by-count":43,"title":["Three novel <i>IGF1R<\/i> mutations in microcephalic patients with prenatal and postnatal growth impairment"],"prefix":"10.1111","volume":"82","author":[{"given":"Matias","family":"Juanes","sequence":"first","affiliation":[{"name":"Endocrinology Service Hospital de Pediatr\u00eda Garrahan Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Guercio","sequence":"additional","affiliation":[{"name":"Endocrinology Service Hospital de Pediatr\u00eda Garrahan Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roxana","family":"Marino","sequence":"additional","affiliation":[{"name":"Endocrinology Service Hospital de Pediatr\u00eda Garrahan Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esperanza","family":"Berensztein","sequence":"additional","affiliation":[{"name":"Endocrinology Service Hospital de Pediatr\u00eda Garrahan Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana M\u00f3nica","family":"Warman","sequence":"additional","affiliation":[{"name":"Endocrinology Service Hospital de Pediatr\u00eda Garrahan Buenos Aires 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