期刊
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
卷 95, 期 5, 页码 2316-2324出版社
ENDOCRINE SOC
DOI: 10.1210/jc.2009-2404
关键词
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资金
- Medical Faculty of the University of Leipzig
- Deutsche Forschungsgemeinschaft (Bonn, Germany) [PF 225/3-1, KFO 152]
- Pfizer
- Novo Nordisk
- Ipsen
- Merck Serono
- Kompetenznetze Adipositas und Diabetes, Bundesministerium fur Bildung und Forschung (Berlin, Germany)
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)
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