About 80% of short children are not deficient in endogenous growth hormone (GH) and termed idiopathic short stature (ISS). The causes of impaired growth in children with ISS are various. Short stature and low insulin-like growth factor-I (IGF-I) concentration despite normal to high GH concentration suggest impaired GH effect. The prototypical GH insensitivity syndrome was described and characterized by the absent or defective GH receptors. Growth retardation resulting from biologically inactive GH was also described, but the molecular basis of biologically inactive GH has remained unclear. Recently, two unique point mutations in the GH-1 gene in the children with short stature whose GH were supposed as bioinactive were reported. Mutant GH R77C not only failed to stimulate tyrosine phosphorylation by itself, but it also inhibited the activity of wild-type GH. This mutant GH exerted an antagonistic effect. Another mutant D112G was only bio-inactive. This case was a typical Kowarski syndrome. The molecular heterogeneity of mutant GH reflected clinical phenotype of bioinactive GH syndrome.

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