{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T11:23:05Z","timestamp":1789989785551,"version":"4.0.1"},"reference-count":38,"publisher":"The Endocrine Society","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Background: Mutations in the IGF-I receptor (IGF1R) gene can be responsible for intrauterine and postnatal growth disorders.<\/jats:p><jats:p>Objective: Here we report on a novel mutation in the IGF1R gene in a female patient. The aim of our study was to analyze the functional impact of this mutation.<\/jats:p><jats:p>Patient: At birth, the girl\u2019s length was 47 cm [\u22121.82 sd score (SDS)], and her weight was 2250 g (\u22122.26 SDS). Clinical examination revealed microcephaly and retarded cognitive development. She showed no postnatal catch-up growth but had relatively high IGF-I levels (+1.83 to +2.17 SDS).<\/jats:p><jats:p>Results: Denaturing HPLC screening and direct DNA sequencing disclosed a heterozygous missense mutation resulting in an amino acid exchange from valine to glutamic acid at position 599 (V599E-IGF1R). Using various cell systems, we found that the V599E-IGF1R mutant was not tyrosine phosphorylated and had an impaired downstream signaling in the presence of IGF-I. Flow cytometry and live cell confocal laser scanning microscopy revealed a lack of cell surface expression due to an extensive retention of V599E-IGF1R proteins within the endoplasmic reticulum.<\/jats:p><jats:p>Conclusion: The V599E-IGF1R mutation interferes with the receptor\u2019s trafficking path, thereby abrogating proreceptor processing and plasma membrane localization. Diminished cell surface receptor density solely expressed from the patient\u2019s wild-type allele is supposed to lead to insufficient IGF-I signaling. We hypothesize that this mechanism results in intrauterine and postnatal growth retardation of the affected patient. The reported retention of the nascent IGF1R in the endoplasmic reticulum presents a novel mechanism of IGF-I resistance.<\/jats:p>","DOI":"10.1210\/jc.2009-2404","type":"journal-article","created":{"date-parts":[[2010,3,31]],"date-time":"2010-03-31T20:59:44Z","timestamp":1270069184000},"page":"2316-2324","source":"Crossref","is-referenced-by-count":61,"title":["A Heterozygous Mutation of the Insulin-Like Growth Factor-I Receptor Causes Retention of the Nascent Protein in the Endoplasmic Reticulum and Results in Intrauterine and Postnatal Growth Retardation"],"prefix":"10.1210","volume":"95","author":[{"given":"Tillmann","family":"Wallborn","sequence":"first","affiliation":[{"name":"University Hospital for Children and Adolescents (T.W., J.Kl., T.K., M.S., E.M., W.K., R.P.), University of Leipzig, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Wu\u0308ller","sequence":"additional","affiliation":[{"name":"University Hospital Aachen (S.W.), Department for Paediatric and Adolescent Medicine, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju\u0308rgen","family":"Klammt","sequence":"additional","affiliation":[{"name":"University Hospital for Children and Adolescents (T.W., J.Kl., T.K., M.S., E.M., W.K., R.P.), University of Leipzig, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tassilo","family":"Kruis","sequence":"additional","affiliation":[{"name":"University Hospital for Children and Adolescents (T.W., J.Kl., T.K., M.S., E.M., W.K., R.P.), University of Leipzig, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju\u0308rgen","family":"Kratzsch","sequence":"additional","affiliation":[{"name":"Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics (J.Kr.), University of Leipzig, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Sozialpa\u0308diatrisches Zentrum Garmisch-Partenkirchen (G.S.), 82467 Garmisch-Partenkirchen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Schlicke","sequence":"additional","affiliation":[{"name":"University Hospital for Children and Adolescents (T.W., J.Kl., T.K., M.S., E.M., W.K., R.P.), University of Leipzig, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Mu\u0308ller","sequence":"additional","affiliation":[{"name":"University Hospital for Children and Adolescents (T.W., J.Kl., T.K., M.S., E.M., W.K., R.P.), University of Leipzig, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hildegard","family":"Schmitz van de Leur","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry, 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