INSULIN-LIKE GROWTH-FACTOR-I RECEPTOR EXPRESSION AND FUNCTION IN FIBROBLASTS FROM 2 PATIENTS WITH DELETION OF THE DISTAL LONG ARM OF CHROMOSOME-15

Most patients with deletion of the distal long arm of chromosome 15 ha ve intrauterine growth retardation and postnatal growth deficiency in addition to developmental abnormalities. It has been proposed that the absence of one copy of the insulin-like growth factor I (IGF-I) recep tor gene may play a role in the growth deficiency seen in this syndrom e. To address this question we examined IGF-I receptor expression and function in fibroblasts from two patients with deletion of the distal long arm of chromosome 15 (15q26.1-->qter). Quantitative Southern blot analysis of the IGF-I receptor gene was performed on HindIII digests of fibroblast DNA. Radioactivity in the 1.7-kilobase receptor fragment in the two patients was 55% and 51% of the values in controls, consis tent with the absence of one copy of the IGF-I receptor gene. IGF-I re ceptor messenger ribonucleic acid levels were quantitated by a solutio n hybridization/nuclease protection assay. Receptor messenger ribonucl eic acid levels in the two patients were 45% and 52% of the values in controls. Northern blotting demonstrated normal size IGF-I receptor tr anscripts and affinity crosslinking of [I-125]]IGF-I to Triton X-100-s olubilized fibroblasts demonstrated a normal size receptor in the pati ents. Analysis of placental membranes prepared from one patient reveal ed no difference in [I-125]IGF-I binding. In the patients' fibroblasts , however, binding of [I-125]long [R(3)]-IGF-I to the IGF-I receptor w as significantly reduced, as assessed by the amount of radioactivity c ompeted by the monoclonal antibody alpha IR-3 or insulin and Scatchard analysis of binding data. To assess IGF-I receptor function, stimulat ion of [alpha-1-C-14]methylaminoisobutyric acid transport and stimulat ion of [methyl-H-3]thymidine incorporation into DNA by a full range of IGF-I concentrations was examined in patient and control fibroblasts. There was a significant decrease in the maximal response to IGF-I in both assays for one of the two patients when data were expressed as fo ld response over the basal value. However, there was no evidence for i mpairment of response to IGF-I in either patient's fibroblasts when da ta were expressed as net stimulation (maximal response minus basal). I n conclusion, although IGF-I receptor expression was decreased in fibr oblasts from two patients with deletion of the distal long arm of chro mosome 15, we were unable to provide conclusive evidence for impairmen t of the biological response to IGF-I.