{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T11:23:35Z","timestamp":1789989815355,"version":"4.0.1"},"reference-count":30,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2013,1,7]],"date-time":"2013-01-07T00:00:00Z","timestamp":1357516800000},"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":[[2013,2]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Context<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">I<\/jats:styled-content> is essential for normal human growth and mediates its effects through the <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>1<jats:styled-content style=\"fixed-case\">R<\/jats:styled-content>. <jats:styled-content style=\"fixed-case\"><jats:italic>IGF1R<\/jats:italic><\/jats:styled-content> mutations have been associated with varying degrees of intrauterine and postnatal growth retardation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To identify <jats:styled-content style=\"fixed-case\"><jats:italic>IGF1R<\/jats:italic><\/jats:styled-content> gene mutations in a short\u2010statured family with intrauterine growth retardation and microcephaly.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Direct <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> sequencing was used to identify <jats:styled-content style=\"fixed-case\"><jats:italic>IGF1R<\/jats:italic><\/jats:styled-content> mutations. Multiplex ligation\u2010dependent probe amplification analyses were performed for deletions and duplications of all <jats:styled-content style=\"fixed-case\"><jats:italic>IGF1R<\/jats:italic><\/jats:styled-content> exons. Functional studies were conducted to assess mutation pathogenicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A novel heterozygous <jats:styled-content style=\"fixed-case\"><jats:italic>IGF1R<\/jats:italic><\/jats:styled-content> missense mutation in exon 7 (c.<jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>1549<jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>, p.<jats:styled-content style=\"fixed-case\">Y<\/jats:styled-content>487<jats:styled-content style=\"fixed-case\">F<\/jats:styled-content>) was identified in a short\u2010statured girl with severe prenatal growth retardation and microcephaly. The same mutation was also identified in her mother, who presented prenatal and postnatal growth failure, and her short\u2010statured maternal grandmother, both of whom exhibited microcephaly. The index case showed a partial response to rh<jats:styled-content style=\"fixed-case\">GH<\/jats:styled-content>. Functional studies performed in dermal fibroblasts from the index case and her mother showed normal <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">I<\/jats:styled-content> binding; however, <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">I<\/jats:styled-content> activation of intracellular signalling measured as <jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content> and extracellular signal\u2013regulated kinase phosphorylation was markedly reduced, with patients' values being lower than those of her mother. <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">I<\/jats:styled-content> stimulation of <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> synthesis was significantly reduced compared with controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our results show a novel missense mutation in the <jats:styled-content style=\"fixed-case\"><jats:italic>IGF1R<\/jats:italic><\/jats:styled-content> gene (c.<jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>1549<jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>, p.<jats:styled-content style=\"fixed-case\">Y<\/jats:styled-content>487<jats:styled-content style=\"fixed-case\">F<\/jats:styled-content>) associated with prenatal and postnatal growth failure and microcephaly in the context of familial short stature. The functional studies are in line with the inactivation of one copy of the <jats:styled-content style=\"fixed-case\"><jats:italic>IGF1R<\/jats:italic><\/jats:styled-content> gene with variable expression within the same family.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.1365-2265.2012.04481.x","type":"journal-article","created":{"date-parts":[[2012,6,28]],"date-time":"2012-06-28T08:22:00Z","timestamp":1340871720000},"page":"255-262","source":"Crossref","is-referenced-by-count":24,"title":["Familial short stature and intrauterine growth retardation associated with a novel mutation in the <scp>IGF<\/scp>\u2010<scp>I<\/scp> receptor (<i><scp>IGF1R<\/scp><\/i>) gene"],"prefix":"10.1111","volume":"78","author":[{"given":"Jos\u00e9 I.","family":"Labarta","sequence":"first","affiliation":[{"name":"Endocrinology Unit Department of Pediatrics Hospital Infantil Universitario \u201cMiguel Servet\u201d Zaragoza 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