Ad. Goddard et al., MUTATIONS OF THE GROWTH-HORMONE RECEPTOR IN CHILDREN WITH IDIOPATHIC SHORT STATURE, The New England journal of medicine, 333(17), 1995, pp. 1093-1098
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.