Context and Objective: A single missense mutation in the GH-1 gene converting codon 77 from arginine (R) to cysteine (C) yields a mutant GH-R77C peptide, which was described as natural growth hormone antagonist.

Design, Setting, Patients: Heterozygosity for GH-R77C / wt-GH was identified in a Syrian family. The index patient, a boy, was referred for assessment of his short stature (-2.5 SDS) and partial GH-insensitivity was diagnosed. His mother and grandfather were also carrying the same mutation and showed partial GH-insensitivity with modest short stature.

Interventions and Results: Functional characterization of the GH-R77C was performed through studies of GH-receptor binding and activation of Jak2/Stat5 pathway. No differences in the binding affinity and bioactivity between wt-GH and GH-R77C were found. Similarly, cell viability and proliferation after expression of both GH peptides in AtT-20 cells were identical. Quantitative confocal microscopy analysis revealed no significant difference in the extent of subcellular co-localization between wt-GH and GH-R77C with either ER, Golgi, or secretory vesicles. Further studies demonstrated a reduced capability of GH-R77C to induce GHR/GHBP gene transcription rate when compared to wt-GH.

Conclusion: Reduced GHR/GHBP expression might be a possible cause for the partial GH-insensitivity with delay in growth and pubertal development found in our patients. In addition, this group of patients deserves further attention, because they could represent a distinct clinical entity underlining that an altered GH peptide may also have a direct impact on GHR/GHBP gene expression causing partial GH-insensitivity.