MUTATIONS OF THE GROWTH-HORMONE RECEPTOR IN CHILDREN WITH IDIOPATHIC SHORT STATURE

Background. Short stature in children who are not deficient in growth hormone (GH) is probably caused by a variety of defects. Some children with idiopathic short stature have low serum concentrations of GH-bin ding protein, which is derived from the GH receptor. The possibility t hat low serum concentrations of GH-binding protein might indicate part ial insensitivity to GH led us to investigate possible defects in the gene for the GH receptor in children with idiopathic short stature and low serum concentrations of GH-binding protein. Methods. We studied 1 4 children with idiopathic short stature who were selected on the basi s of normal GH secretion and low serum concentrations of GH-binding pr otein. Analysis of single-strand conformation polymorphisms and DNA se quencing were both used to identify mutations in the GH-receptor gene. Results. Mutations in the region of the GH-receptor gene that codes f or the extracellular domain of the receptor were found in 4 of the 14 children, but in none of 24 normal subjects. One of the four children with mutations was a compound heterozygote, with one mutation that red uced the affinity of the receptor for GH and a second mutation that ma y affect a function other than ligand binding. The remaining three chi ldren had single mutations in one allele of the gene. One mutation int roduced a premature termination codon, and two caused substitutions of single amino acids in a structurally conserved domain of the receptor . Conclusions. Some children with idiopathic short stature may have pa rtial insensitivity to GH due to mutations in the GH-receptor gene.