Novel inactivating mutations in the GH secretagogue receptor gene in patients with constitutional delay of growth and puberty

<jats:sec><jats:title>Background</jats:title><jats:p>A limited number of mutations in the GH secretagogue receptor gene (<jats:italic>GHSR</jats:italic>) have been described in patients with short stature.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>To analyze <jats:italic>GHSR</jats:italic> in idiopathic short stature (ISS) children including a subgroup of constitutional delay of growth and puberty (CDGP) patients.</jats:p></jats:sec><jats:sec><jats:title>Subjects and methods</jats:title><jats:p>The <jats:italic>GHSR</jats:italic> coding region was directly sequenced in 96 independent patients with ISS, 31 of them with CDGP, in 150 adults, and in 197 children with normal stature. The pharmacological consequences of <jats:italic>GHSR</jats:italic> non-synonymous variations were established using <jats:italic>in vitro</jats:italic> cell-based assays.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Five different heterozygous point variations in <jats:italic>GHSR</jats:italic> were identified (c.−6 G>C, c.251G>T (p.Ser84Ile), c.505G>A (p.Ala169Thr), c.545 T>C (p.Val182Ala), and c.1072G>A (p.Ala358Thr)), all in patients with CDGP. Neither these allelic variants nor any other mutations were found in 694 alleles from controls. Functional studies revealed that two of these variations (p.Ser84Ile and p.Val182Ala) result in a decrease in basal activity that was in part explained by a reduction in cell surface expression. The p.Ser84Ile mutation was also associated with a defect in ghrelin potency. These mutations were identified in two female patients with CDGP (at the age of 13 years, their height SDS were −2.4 and −2.3). Both patients had normal progression of puberty and reached normal adult height (height SDS of −0.7 and −1.4) without treatment.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>This is the first report of <jats:italic>GHSR</jats:italic> mutations in patients with CDGP. Our data raise the intriguing possibility that abnormalities in ghrelin receptor function may influence the phenotype of individuals with CDGP.</jats:p></jats:sec>