In:
The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 95, No. 5 ( 2010-05-01), p. 2316-2324
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0021-972X
,
1945-7197
DOI:
10.1210/jc.2009-2404
Language:
English
Publisher:
The Endocrine Society
Publication Date:
2010
detail.hit.zdb_id:
2026217-6
