Mono-allelic expression of the IGF-I receptor does not affect IGF responses in human fibroblasts.
OBJECTIVE
It has been suggested that mono-allelic deletion of the IGF-I receptor gene is causally related to severe intrauterine and postnatal growth deficiency whereas no IGF-I resistance was observed in the patients' fibroblasts. The expression and regulation of the growth-modulating IGF binding proteins (IGFBPs) have been investigated in serum and fibroblasts of a short girl with mono-allelic loss of the distal long arm of chromosome 15 (15q26.1-qter).


METHODS
The mono-allelic loss of the IGF-I receptor (IGF1R) gene was confirmed in a child with prenatal and severe postnatal growth retardation by fluorescence in situ hybridization, and was evaluated on the protein level in fibroblasts of the patient by FACS analysis and IGF cross-linkage. Additionally, expression of IGFBPs and cell-mediated degradation of IGFBP-3 were examined in the patient's fibroblasts.


RESULTS
Levels of GH, IGF-I, and IGFBP-3 were above the 95th percentile in the serum of the 3-year-old girl with a mono-allelic deletion of the IGF1R gene, suggesting IGF-I resistance. In the patient's fibroblasts the IGF-I receptor concentration was half that in control cells. Whereas the pattern of secreted IGFBPs in response to IGFs was not altered, the abundance of secreted IGFBPs was higher in the patient's cells than in controls. Moreover, fibroblast-mediated degradation of 125I-labeled IGFBP-3 appears to be reduced in the patient's fibroblasts. The higher abundance of IGFBPs in the patient's fibroblasts might be responsible for the lack of IGF-I-stimulated [alpha-1-14C]methylaminoisobutyric acid transport.


CONCLUSIONS
Our results suggest that the expression and regulation of IGFBPs in tissues from patients with mono-allelic deletion of the IGF-I receptor gene may lead to IGF sequestration and contribute to IGF-I resistance and growth retardation.
Children's Hospital, University of Hamburg 20246 Hamburg, Germany.
Elke
E
Hammer
Kerstin
K
Kutsche
Friedrich
F
Haag
Kurt
K
Ullrich
Ralf
R
Sudbrak
Rolf Peter
RP
Willig
Thomas
T
Braulke
Bernd
B
Kubler
D001827:Body Height / Q000235:genetics; D018929:Cell Culture Techniques; D002675:Child, Preschool; D002872:Chromosome Deletion; D002884:Chromosomes, Human, Pair 15; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics*
D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1