Biologically inactive growth hormone caused by an amino acid substitution.

Abstract

Short stature caused by biologically inactive growth hormone (GH) is characterized by lack of GH action despite high immunoassayable GH levels in serum and marked catch-up growth to exogenous GH administration. We found a heterozygous single-base substitution (A → G) in exon 4 of the GH-1 gene of a girl with short stature, clinically suspected to indicate the presence of bioinactive GH and resulting in the substitution of glycine for aspartic acid at codon 112. We confirmed the presence of mutant GH in the serum using isoelectric focusing analysis. The locus of mutation D112G was found within site 2 of the GH molecule in binding with GH receptor (GHR)/GH binding protein (GHBP). The expressed recombinant mutant GH tended to form a 1:1 instead of the 1:2 GH-GHBP complex normally produced by wild-type GH. The formation of a 1:2 GH-GHBP complex is compatible with the dimerization of GHRs by GH, a crucial step in GH signal transduction. Mutant GH was less potent than wild-type GH not only in phosphorylation of tyrosine residues in GHR, janus kinase 2 (JAK2), and signal transducers and activators of transcription 5 (STAT5) in IM-9 cells, but also in metabolic responses of BaF/GM cells, a stable clone transfected with cDNA of the chimera of the extracellular domain of human GHR, the transmembrane and the cytoplasmic domain of the human thrombopoietin receptor. These results indicate that the D112G mutation in the GH-1 gene causes production of bioinactive GH, which prevents dimerization of GHR and is therefore responsible for the patient's short stature. ( J. Clin. Invest.

The effects of recombinant human GH on promoting tumor growth depend on the expression of GH receptor in vivo

“…Owing to the gene homology of human and mice, most research in vivo was found not to be influenced by species specificity of GH (Takahashi et al 1997). In this study, the intrinsic bionomics difference of human gastric cancer cell lines with different GHR expression was not excluded and will be further evaluated in the next paper.…”

An immunologically anomalous but considerably bioactive GH produced by a novel GH1 mutation (p.D116E)

“…Furthermore, since the previously described p.D116A-GH harboring a missense mutation within the GH receptor-binding site 2 has a 5.7-fold lower affinity to the GH receptor than the WT-GH (15), this would argue for a functional importance of the D116 residue and implicate a similar functional alteration of the p.D116E-GH. In addition, although GH1 missense mutations reported to date are relatively rare (16), GH missense MTs, including those within or near the GH receptor binding site 2, frequently have a reduced or altered biological activity (2,4,(17)(18)(19)(20)(21).…”

“…Indeed, GH provocation tests are almost invariably performed in children with short stature (1), and measured serum GH values usually reflect GH bioactivities. However, in a rare condition known as 'bioinactive GH', discrepancy exists between measured GH values and GH bioactivities (2)(3)(4). Thus, this condition is associated with low insulin-like growth factor-1 (IGF-1) values, short stature, and good responses to GH therapy, in the presence of apparently normal to mildly elevated serum GH values.…”

Bases Genéticas dos Distúrbios de Crescimento

“…descreveram duas crianças com fenótipo semelhante aos de crianças com deficiência de GH (baixa estatura severa e níveis baixos de IGF-I), mas que apresentavam secreção elevada de GH, e sugeriram que estas crianças possuíam uma molécula de GH biologicamente inativa (71). Mutações em heterozigose no gene GH-1 que causam a produção de uma molécula anômala de GH com estas características foram descritas em apenas dois casos na literatura (72,73). Esta molécula de GH anômala possui uma afinidade aumentada pela sua proteína carreadora (GHBP) e inibe a ligação da molécula de GH normal ao receptor ou ainda dificulta a dimerização do receptor.…”