168469 20260210085434.0 doi 10.1111/j.1365-2265.2012.04481.x sideral 81190 ART-2013-81190 eng Barrio, E Universidad de Zaragoza (orcid)0000-0001-5603-3045 Familial short stature and intrauterine growth retardation associated with a novel mutation in the IGF-I (IGF1R) receptor gene 2013 Access copy available to the general public Unrestricted Summary: Context IGF-I is essential for normal human growth and mediates its effects through the IGF1R. IGF1R mutations have been associated with varying degrees of intrauterine and postnatal growth retardation. Objective To identify IGF1R gene mutations in a short-statured family with intrauterine growth retardation and microcephaly. Methods Direct DNA sequencing was used to identify IGF1R mutations. Multiplex ligation-dependent probe amplification analyses were performed for deletions and duplications of all IGF1R exons. Functional studies were conducted to assess mutation pathogenicity. Results A novel heterozygous IGF1R missense mutation in exon 7 (c.A1549T, p.Y487F) was identified in a short-statured 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-statured maternal grandmother, both of whom exhibited microcephaly. The index case showed a partial response to rhGH. Functional studies performed in dermal fibroblasts from the index case and her mother showed normal IGF-I binding; however, IGF-I activation of intracellular signalling measured as AKT and extracellular signal–regulated kinase phosphorylation was markedly reduced, with patients’ values being lower than those of her mother. IGF-I stimulation of DNA synthesis was significantly reduced compared with controls. Conclusion Our results show a novel missense mutation in the IGF1R gene (c.A1549T, p.Y487F) 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 IGF1R gene with variable expression within the same family. info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI07-0145 info:eu-repo/semantics/openAccess All rights reserved http://www.europeana.eu/rights/rr-f/ 3.353 2013 ENDOCRINOLOGY & METABOLISM 53 / 121 = 0.438 2013 Q2 T2 info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion Labarta-Aizpún, JI. Universidad de Zaragoza (orcid)0000-0003-2832-2266 Audi, L Fernández-Cancio, M Andaluz, P De Arriba, A (orcid)0000-0002-2865-5813 Puga, B Calvo, MT Mayayo, E Carrascosa, A Ferrández-Longás, A 1003 443 Universidad de Zaragoza Dpto. Anatom.Histolog.Humanas Area Histología 1010 670 Universidad de Zaragoza Dpto. Pediatría Radiol.Med.Fís Área Pediatría 78, 2 (2013), 255-262 Clin. endocrinol. CLINICAL ENDOCRINOLOGY 0300-0664 592093 http://zaguan.unizar.es/record/168469/files/texto_completo.pdf Postprint 1071782 http://zaguan.unizar.es/record/168469/files/texto_completo.jpg?subformat=icon icon Postprint oai:zaguan.unizar.es:168469 articulos driver 2026-02-10-08:48:30 ARTICLE