TY - JOUR
T1 - Abnormal GH receptor signaling in children with idiopathic short stature
AU - Salerno, Mariacarolina
AU - Balestrieri, Barbara
AU - Matrecano, Eliana
AU - Officioso, Annunziata
AU - Rosenfeld, Ron G.
AU - Di Maio, Salvatore
AU - Fimiani, Giorgia
AU - Ursini, Matilde Valeria
AU - Pignata, Claudio
PY - 2001
Y1 - 2001
N2 - Peripheral GH insensitivity may underlie idiopathic short stature in children. As the clinical and biochemical hallmarks of partial GH insensitivity have not yet been clearly elucidated, the identification of such patients is still difficult. We integrated functional, biochemical, and molecular studies to define the more reliable marker(s) of GH insensitivity. In particular, we measured GH receptor transducing properties through GH-induced protein tyrosine phosphorylation in patients' peripheral blood mononuclear cells and performed direct sequencing analysis of GH receptor-coding exons. Five of 14 idiopathic short stature patients with low basal IGF-I levels showed low or absent IGF-I increment after 4 d of GH administration. However, a prolonged GH stimulation induced in 3 of them an increase in IGF-140% above the baseline value. The IGF-binding protein-3 behavior paralleled that of IGF-I. The 2 GH-unresponsive subjects showed an abnormal tyrosine phosphorylation pattern after GH challenge. Sequence analysis of the GH receptor gene revealed a heterozygous mutation resulting in an Arg to Cys change (R161C) in exon 6 in only 1 patient, who had normal GH receptor responsiveness. Our findings indicate that abnormal GH receptor signaling may underlie idiopathic short stature even in the absence of GH receptor mutations. Thus, combining the 4-dIGF-I generation test and the analysis of GH-induced protein tyrosine phosphorylation is a useful tool to help identify idiopathic short stature patients with partial GH insensitivity.
AB - Peripheral GH insensitivity may underlie idiopathic short stature in children. As the clinical and biochemical hallmarks of partial GH insensitivity have not yet been clearly elucidated, the identification of such patients is still difficult. We integrated functional, biochemical, and molecular studies to define the more reliable marker(s) of GH insensitivity. In particular, we measured GH receptor transducing properties through GH-induced protein tyrosine phosphorylation in patients' peripheral blood mononuclear cells and performed direct sequencing analysis of GH receptor-coding exons. Five of 14 idiopathic short stature patients with low basal IGF-I levels showed low or absent IGF-I increment after 4 d of GH administration. However, a prolonged GH stimulation induced in 3 of them an increase in IGF-140% above the baseline value. The IGF-binding protein-3 behavior paralleled that of IGF-I. The 2 GH-unresponsive subjects showed an abnormal tyrosine phosphorylation pattern after GH challenge. Sequence analysis of the GH receptor gene revealed a heterozygous mutation resulting in an Arg to Cys change (R161C) in exon 6 in only 1 patient, who had normal GH receptor responsiveness. Our findings indicate that abnormal GH receptor signaling may underlie idiopathic short stature even in the absence of GH receptor mutations. Thus, combining the 4-dIGF-I generation test and the analysis of GH-induced protein tyrosine phosphorylation is a useful tool to help identify idiopathic short stature patients with partial GH insensitivity.
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U2 - 10.1210/jcem.86.8.7759
DO - 10.1210/jcem.86.8.7759
M3 - Article
C2 - 11502828
AN - SCOPUS:0034889997
SN - 0021-972X
VL - 86
SP - 3882
EP - 3888
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 8
ER -