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

作者：Wallborn Tillmann; Wueller Stefan; Klammt Juergen; Kruis Tassilo; Kratzsch Juergen; Schmidt Gabriele; Schlicke Marina; Mueller Eva; van de Leur Hildegard Schmitz; Kiess Wieland; Pfaeffle Roland

来源：Journal of Clinical Endocrinology & Metabolism, 2010, 95(5): 2316-2324.

DOI：10.1210/jc.2009-2404

Background: Mutations in the IGF-I receptor (IGF1R) gene can be responsible for intrauterine and postnatal growth disorders.
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.
Patient: At birth, the girl's length was 47 cm [-1.82 SD score (SDS)], and her weight was 2250 g (-2.26 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).
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.
Conclusion: The V599E-IGF1R mutation interferes with the receptor's trafficking path, thereby abrogating proreceptor processing and plasma membrane localization. Diminished cell surface receptor density solely expressed from the patient's 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. (J Clin Endocrinol Metab 95: 2316-2324, 2010)

• 出版日期2010-5