Selective receptor-mediated impairment of growth factor activity in neonatal- and X-linked adrenoleukodystrophy patients

Abstract

Abstract Background Neonatal adrenoleukodystrophy (n-ALD) and X-linked ALD (X-ALD) patients present with demyelination, poor growth and progressive mental retardation. Growth factors are known to play a vital role in the development of children. Objective To examine the mitogenic activity of various growth factors in skin fibroblasts from n-ALD and X-ALD patients. Methods Skin fibroblast cultures from n-ALD and X-ALD patients, and controls were treated with 50 ng/mL of platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF) or insulin-like growth factor-1 (IGF-1) to examine DNA synthesis by 5-bromo-2′-deoxyuridine (BrdU) incorporation. Expression of receptors for PDGF, bFGF and IGF-1 was measured by western blotting. Serum levels of IGF-1 were assayed by enzyme-linked immunosorbent assay (ELISA). Results Fibroblasts from n-ALD and X-ALD patients had significantly (p < 0.01) less BrdU incorporation in response to fetal bovine serum (FBS). The mitogenic effect of PDGF, bFGF and IGF-1 was significantly lower in n-ALD as compared to control and X-ALD cells. X-ALD cells showed significant impairment in IGF-1-induced DNA synthesis. Expression of the FGF receptor (FGF-R) was significantly reduced in n-ALD cells. PDGF receptor remained unaffected, and IGF-1 receptor (IGF-1R) expression and serum IGF-1 levels were significantly (p < 0.01) reduced in n-ALD and X-ALD patients as compared to controls. Conclusions Growth factor activity differs in n-ALD and X-ALD patients, with marked impairment of IGF-1 function through receptor down-regulation.