299 a New Syndrome of Short Stature Due to Biologically Inactive but Immunoreactive Growth Hormone

Hayek, Alberto; Peake, Glenn T.; Greenberg, Robert E.

doi:10.1203/00006450-197804001-00304

Cited by 33 publications

(13 citation statements)

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“…The diagnosis of 'syndrome of bioinactive GH' has often been discussed and suggested in short children with the phenotype resembling isolated GHD with normal or even slightly elevated basal GH levels, low IGF1 concentration, and normal catch-up growth on GH replacement therapy. Short stature associated with bioinactive GH was first described by Kowarski et al (12) while additional cases were reported in the 1980s on clinical basis (13,14,15,16,17). Takahashi et al (18) described a heterozygous point mutation in the GH1 gene (D112G) found in a Japanese patient with short stature.…”

Section: Introductionmentioning

confidence: 99%

Short stature in two siblings heterozygous for a novel bioinactive GH mutant (GH-P59S) suggesting that the mutant also affects secretion of the wild-type GH

Petkovic

Miletta

Boot

et al. 2013

European Journal of Endocrinology

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Objective: Short stature caused by biologically inactive GH is clinically characterized by lack of GH action despite normal-high secretion of GH, pathologically low IGF1 concentrations and marked catch-up growth on GH replacement therapy. Design and methods: Adopted siblings (girl and a boy) of unknown family history were referred for assessment of short stature (K4.5 and K5.6 SDS) at the age of 10 and 8.1 years respectively. They had delayed bone ages (6.8 and 4.5 years), normal GH peaks at stimulation tests, and severely reduced IGF1 concentrations (K3.5 and K4.0 SDS). Genetic analysis of the GH1 gene showed a heterozygous P59S mutation at position involved in binding to GH receptor (GHR). Results: Isoelectric focusing analysis of secreted GH in patient serum revealed the presence of higher GH-P59S peak compared with that of wt-GH. Furthermore, computational simulation of GH-P59S binding to GHR suggested problems in correct binding of the mutant to the GHR. In vitro GHR binding studies revealed reduced binding affinity of GH-P59S for GHR (IC 50 , 30 ng/ml) when compared with the wt-GH (IC 50 , 11.8 ng/ml) while a significantly decreased ability of the mutant to activate the Jak2/Stat5 signaling pathway was observed at physiological concentrations of 25-100 ng/ml. Conclusions: The clinical and biochemical data of our patients support the diagnosis of partial bioinactive GH syndrome. The higher amount of GH-P59S secreted in their circulation combined with its impact on the wt-GH function on GHR binding and signaling may alter GHR responsiveness to wt-GH and could ultimately explain severe short stature found in our patients.

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Section: Introductionmentioning

confidence: 99%

Short stature in two siblings heterozygous for a novel bioinactive GH mutant (GH-P59S) suggesting that the mutant also affects secretion of the wild-type GH

Petkovic

Miletta

Boot

et al. 2013

European Journal of Endocrinology

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“…There have been several reports that bioinactive GH may be responsible for growth retardation (1)(2)(3)(4)(5)(6)(7)(8). However, the molecular basis of bioinactive GH has not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

Biologically inactive growth hormone caused by an amino acid substitution.

Takahashi¹,

Shirono²,

Arisaka³

et al. 1997

J. Clin. Invest.

107

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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.

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“…A disorder which clinically completely corresponds to CDGA is growth retardation due to bioinactive GH, a condition first described by Kowarski et al [50] and Hayek et al [51]. Biochemically the circulating GH is abnormal, biologically it is inactive [52,53], These chil dren also grow at a normal rate if put on recombinant hGH.…”

Section: Kowarski's Syndromementioning

confidence: 99%

Therapy with Growth Hormone – Old and New Indications

Bierich

1989

Horm Res

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Pituitary dwarfism with severe growth hormone deficiency (GHD) represents the classical indication for treatment by recombinant human growth hormone (hGH). With continuous GH replacement and early start of treatment, normal adult height can be achieved. During puberty the dosage of hGH administered should be increased. Numerous growth disorders do not coincide with major GHD as determined by provocative tests but only with diminished spontaneous hormone secretion. Typical examples are constitutional delay of growth and adolescence and growth retardation after irradiation of the skull. Also in these disorders treatment by recombinant hGH in replacement doses renders favorable results. The more normal the spontaneous GH secretion is, e.g. in familial short stature and in skeletal dysplasias, the higher doses of GH are needed to stimulate growth. For treatment of patients with Turner’s syndrome a combined therapy with high doses of GH and with oxandrolone has proven rather effective. With endogenous and exogenous hypercortisolism the metabolic balance is shifted towards catabolism and spontaneous GH secretion is depressed. In such situations, e.g. after severe traumas, operations, infections and combustions, administration of GH can be rather helpful. Recent trials in children with stunted growth due to chronic renal insufficiency show that it is possible also in this condition to effectively stimulate growth by hGH.

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299 a New Syndrome of Short Stature Due to Biologically Inactive but Immunoreactive Growth Hormone

Cited by 33 publications

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Short stature in two siblings heterozygous for a novel bioinactive GH mutant (GH-P59S) suggesting that the mutant also affects secretion of the wild-type GH

Short stature in two siblings heterozygous for a novel bioinactive GH mutant (GH-P59S) suggesting that the mutant also affects secretion of the wild-type GH

Biologically inactive growth hormone caused by an amino acid substitution.

Therapy with Growth Hormone – Old and New Indications

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299 a New Syndrome of Short Stature Due to Biologically Inactive but Immunoreactive Growth Hormone

Cited by 33 publications

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Short stature in two siblings heterozygous for a novel bioinactive GH mutant (GH-P59S) suggesting that the mutant also affects secretion of the wild-type GH

Short stature in two siblings heterozygous for a novel bioinactive GH mutant (GH-P59S) suggesting that the mutant also affects secretion of the wild-type GH

Biologically inactive growth hormone caused by an amino acid substitution.

Therapy with Growth Hormone &ndash; Old and New Indications

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Therapy with Growth Hormone – Old and New Indications