A novel GH-1 gene mutation (GH-P59L) causes partial GH deficiency type II combined with bioinactive GH syndrome

Despite the differences in the main characteristics between the autosomal dominant form of GH deficiency (IGHD II) and the bioinactive GH syndrome, a common feature of both is their impact on linear growth leading to short stature in all affected patients.

The index patient, a boy, was referred for assessment of his short stature (-2.54 SD score) and a delayed bone age of 5.9 yrs at the chronological age of 7.7 yrs. The GHD was confirmed by standard GH provocation tests, which revealed modestly reduced GH and IGF-I concentrations. Further genetic analysis of GH-1 gene identified heterozygosity for GH-P59L mutation. The secretion of the GH-P59L following stimulation with forskolin was investigated and compared to that of the wt-GH after expression of both GH variants in AtT-20 cells. Based on the position of P59L mutation that lies within a patch of residues composing the GH binding site 1 for GHR, we performed the analysis of GH-P59L binding to GHR by in silico mutagenesis and molecular dynamics simulations, which suggested possible problems in correct binding of GH-P59L to the GHR. Therefore, the functional characterization of this GH mutant was assessed through studies of GHR binding and activation of Jak2/Stat5 signaling pathway.

In line with the clinical data of the patient GH deficiency is suggested, underlined by GH-secretion studies revealing a moderate difference in secretion between GH-P59L and wt-GH. In addition, further functional characterization of the GH-P59L by studies of GH-receptor binding and activation of Jak2/Stat5 pathway presented with a reduced binding affinity of GH-P59L for GHR and decreased bioactivity compared to the wt-GH.

The clinical data of the patient combined with the laboratory data support the diagnosis of partial IGHD type II. Since the GH deficiency was not total, additional binding and signaling studies were performed, which revealed that the GH-P59L variant displays some of the common features of bioinactive GH syndrome. Taken together, in this study we report a patient suffering from the combination of two growth disorders (alteration of secretion as well as bioactivity) caused by a GH-1 gene alteration highlighting the necessity of functional analysis of any GH variant, despite the presence of obvious clinical features of IGHD type II.