Mono-allelic expression of the IGF-I receptor does not affect IGF responses in human fibroblasts

Abstract

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). Patient and 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-yearold 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 125 I-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 [a-1-14 C]methylaminoisobutyric acid transport. Conclusion: 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.European Journal of Endocrinology 151 521-529

Clinical and Functional Characteristics of the Human Arg59Ter Insulin-Like Growth Factor I Receptor (IGF1R) Mutation: Implications for a Gene Dosage Effect of the Human IGF1R

“…Common phenotypic features of these children include intrauterine growth retardation, postnatal growth failure, microcephaly, facial abnormalities (high arched palate, abnormal ears, and hypertelorism), skeletal abnormalities (clinodactyly, club feet, and scoliosis), and mental retardation. In vitro, fibroblasts from patients with partial 15q26.13qter monosomy display decreased IGF-I ligand binding and IGF-IR tyrosine kinase activation, whereas those from trisomy 15q26.13qter patients display increased IGF-IR phosphorylation (17,21). These data are consistent with an IGF-IR gene dosage effect of the human IGF1R gene, but leave unresolved the role of the IGF1R vs. other genes within the affected region of chromosome 15.…”

Expanding Genetic and Functional Diagnoses of <b><i>IGF1R</i></b> Haploinsufficiencies

“…For P2, SNP microarray analysis identified an unique heterozygous interstitial deletion of approximately 0.282 Mb on chromosome 15 [46 XY del(15)q26.3(99,438,083–99,720,341)]. This region includes exons 4 to 21 of the IGF1R gene (Figure 2B), the deletion of which resulted in loss of ~75% of the IGF1R coding sequences, in addition to three other genes that have unknown phenotypic effects ( PGPEP1L, SYNM and TTC23) .…”

“…Analysis was subsequently expanded to CNV discovery, applying the XHMM algorithm (17). A total of 27 CNVs (16 deletions and 11 duplications) were successfully detected in the patient’s sample, including a large 4.492 Mb heterozygous deletion on chromosome 15 [46 XX del(15)(q26.2:qter)(97,970,832–102,463,314)] (Figure 2C). The CNV was not present in either the parents, or in the 189 additional exomes that were simultaneously analyzed, suggesting the 4.492 Mb deletion was de novo in P3.…”

“…Co-segregation of the heterozygous 15q23.3 deletion and NF1 phenotype in the family, half-shaded. (C) De novo heterozygous 4.492 Mb deletion on chromosome 15 [46 XX del(15)(q26.2:qter)(97,970,832–102,463,314)] identified in P3.…”

“…Ligand association leads to IGFIR autophosphorylation and activation of multiple downstream signaling pathways, including the phosphatidylinositol 3-kinase/AKT and MAPK/ERK pathways important for cell survival and growth (10). In an I GF1R haploinsufficiency state, IGF-I-induced IGF1R signaling is reduced (11–13), although binding of IGF-I may remain normal (14,15), further stressing the necessity of bi-allelic expression of the IGF1R gene for full biological activity.…”