BACKGROUND: A limited number of mutations in the GH secretagogue receptor gene (GHSR) have been described in patients with short stature. Objective To analyze GHSR in idiopathic short stature (ISS) children including a subgroup of constitutional delay of growth and puberty (CDGP) patients. SUBJECTS AND METHODS: The GHSR 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 GHSR non-synonymous variations were established using in vitro cell-based assays. RESULTS: Five different heterozygous point variations in GHSR 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. CONCLUSION: This is the first report of GHSR 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.
BACKGROUND: A limited number of mutations in the GH secretagogue receptor gene (GHSR) have been described in patients with short stature. Objective To analyze GHSR in idiopathic short stature (ISS) children including a subgroup of constitutional delay of growth and puberty (CDGP) patients. SUBJECTS AND METHODS: The GHSR 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 GHSR non-synonymous variations were established using in vitro cell-based assays. RESULTS: Five different heterozygous point variations in GHSR 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. CONCLUSION: This is the first report of GHSR 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.
Authors: Diana L Cousminer; Jaakko T Leinonen; Antti-Pekka Sarin; Himanshu Chheda; Ida Surakka; Karoliina Wehkalampi; Pekka Ellonen; Samuli Ripatti; Leo Dunkel; Aarno Palotie; Elisabeth Widén Journal: PLoS One Date: 2015-06-01 Impact factor: 3.240
Authors: Sasha R Howard; Roberto Oleari; Ariel Poliandri; Vasiliki Chantzara; Alessandro Fantin; Gerard Ruiz-Babot; Louise A Metherell; Claudia P Cabrera; Michael R Barnes; Karoliina Wehkalampi; Leonardo Guasti; Christiana Ruhrberg; Anna Cariboni; Leo Dunkel Journal: J Clin Endocrinol Metab Date: 2018-09-01 Impact factor: 5.958