Primary Growth Hormone (GH) insensitivity and insulin-like growth factor deficiency caused by novel compound heterozygous mutations of the GH receptor gene: Genetic and functional studies of simple and compound heterozygous states

Peng Fang, Stefan Riedl, Serge Amselem, Katherine L. Pratt, Brian M. Little, Gabriele Haeusler, Vivian Hwa, Herwig Frisch, Ronald (Ron) Rosenfeld

Research output: Contribution to journalArticle

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Abstract

Context: Primary GH insensitivity (GHI) or Laron syndrome, caused by mutations of the GH receptor (GHR) gene, has a clinical phenotype of postnatal growth failure associated with normal elevated serum concentrations of GH and low serum levels of IGF-I. Objective: We investigated the clinical and biochemical implications of molecular defects in the GHR gene in an Austrian family with two daughters who were GHI. Patients: Patient 1 [height, -4.8 SD score (SDS)] and patient 2 (height, -5.0 SDS) had elevated circulating levels of GH, low-normal levels of GH-binding protein, and abnormally low IGF-I (-5.0 SDS and -2.6 SDS, respectively) and IGF-binding protein-3 (-2.6 SDS and -2.0 SDS, respectively). Results: Both patients carry novel compound, missense, heterozygous GHR mutations, C94S and H150Q. In vitro reconstitution experiments demonstrated that whereas each of the mutants could be stably expressed, GHR(C94S) lost its affinity for GH and could neither activate signal transducer and activator of transcription (STAT)-5b nor drive STAT5b-dependent gene transcription in response to GH (1-100 ng/ml). GHR(H150Q) showed normal affinity for GH but impaired capacity for signal transduction. The compound heterozygote and C94S heterozygote, but not the H150Q heterozygote, showed significant deficiency in activating GH-induced gene expression, corroborating diminished GH-induced STAT5b activation in fibroblasts carrying GHR(C94S) as either a compound heterozygote (in the patients) or a simple heterozygote (in one parent). Conclusions: Each of the compound heterozygous mutations contributed additively to the pathological condition seen in the patients, and the more detrimental of the two mutations, C94S, may cause (partial) primary GHI, even in a heterozygous state.

Original languageEnglish (US)
Pages (from-to)2223-2231
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Volume92
Issue number6
DOIs
StatePublished - Jun 2007

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Somatotropin Receptors
Somatomedins
Growth Hormone
Genes
Heterozygote
Mutation
Laron Syndrome
Insulin-Like Growth Factor I
STAT5 Transcription Factor
Insulin-Like Growth Factor Binding Protein 3
Signal transduction
Serum
Nuclear Family
Transcription
Fibroblasts
Gene expression
Signal Transduction
Phenotype
Chemical activation
Gene Expression

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Primary Growth Hormone (GH) insensitivity and insulin-like growth factor deficiency caused by novel compound heterozygous mutations of the GH receptor gene : Genetic and functional studies of simple and compound heterozygous states. / Fang, Peng; Riedl, Stefan; Amselem, Serge; Pratt, Katherine L.; Little, Brian M.; Haeusler, Gabriele; Hwa, Vivian; Frisch, Herwig; Rosenfeld, Ronald (Ron).

In: Journal of Clinical Endocrinology and Metabolism, Vol. 92, No. 6, 06.2007, p. 2223-2231.

Research output: Contribution to journalArticle

Fang, Peng ; Riedl, Stefan ; Amselem, Serge ; Pratt, Katherine L. ; Little, Brian M. ; Haeusler, Gabriele ; Hwa, Vivian ; Frisch, Herwig ; Rosenfeld, Ronald (Ron). / Primary Growth Hormone (GH) insensitivity and insulin-like growth factor deficiency caused by novel compound heterozygous mutations of the GH receptor gene : Genetic and functional studies of simple and compound heterozygous states. In: Journal of Clinical Endocrinology and Metabolism. 2007 ; Vol. 92, No. 6. pp. 2223-2231.
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abstract = "Context: Primary GH insensitivity (GHI) or Laron syndrome, caused by mutations of the GH receptor (GHR) gene, has a clinical phenotype of postnatal growth failure associated with normal elevated serum concentrations of GH and low serum levels of IGF-I. Objective: We investigated the clinical and biochemical implications of molecular defects in the GHR gene in an Austrian family with two daughters who were GHI. Patients: Patient 1 [height, -4.8 SD score (SDS)] and patient 2 (height, -5.0 SDS) had elevated circulating levels of GH, low-normal levels of GH-binding protein, and abnormally low IGF-I (-5.0 SDS and -2.6 SDS, respectively) and IGF-binding protein-3 (-2.6 SDS and -2.0 SDS, respectively). Results: Both patients carry novel compound, missense, heterozygous GHR mutations, C94S and H150Q. In vitro reconstitution experiments demonstrated that whereas each of the mutants could be stably expressed, GHR(C94S) lost its affinity for GH and could neither activate signal transducer and activator of transcription (STAT)-5b nor drive STAT5b-dependent gene transcription in response to GH (1-100 ng/ml). GHR(H150Q) showed normal affinity for GH but impaired capacity for signal transduction. The compound heterozygote and C94S heterozygote, but not the H150Q heterozygote, showed significant deficiency in activating GH-induced gene expression, corroborating diminished GH-induced STAT5b activation in fibroblasts carrying GHR(C94S) as either a compound heterozygote (in the patients) or a simple heterozygote (in one parent). Conclusions: Each of the compound heterozygous mutations contributed additively to the pathological condition seen in the patients, and the more detrimental of the two mutations, C94S, may cause (partial) primary GHI, even in a heterozygous state.",
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T1 - Primary Growth Hormone (GH) insensitivity and insulin-like growth factor deficiency caused by novel compound heterozygous mutations of the GH receptor gene

T2 - Genetic and functional studies of simple and compound heterozygous states

AU - Fang, Peng

AU - Riedl, Stefan

AU - Amselem, Serge

AU - Pratt, Katherine L.

AU - Little, Brian M.

AU - Haeusler, Gabriele

AU - Hwa, Vivian

AU - Frisch, Herwig

AU - Rosenfeld, Ronald (Ron)

PY - 2007/6

Y1 - 2007/6

N2 - Context: Primary GH insensitivity (GHI) or Laron syndrome, caused by mutations of the GH receptor (GHR) gene, has a clinical phenotype of postnatal growth failure associated with normal elevated serum concentrations of GH and low serum levels of IGF-I. Objective: We investigated the clinical and biochemical implications of molecular defects in the GHR gene in an Austrian family with two daughters who were GHI. Patients: Patient 1 [height, -4.8 SD score (SDS)] and patient 2 (height, -5.0 SDS) had elevated circulating levels of GH, low-normal levels of GH-binding protein, and abnormally low IGF-I (-5.0 SDS and -2.6 SDS, respectively) and IGF-binding protein-3 (-2.6 SDS and -2.0 SDS, respectively). Results: Both patients carry novel compound, missense, heterozygous GHR mutations, C94S and H150Q. In vitro reconstitution experiments demonstrated that whereas each of the mutants could be stably expressed, GHR(C94S) lost its affinity for GH and could neither activate signal transducer and activator of transcription (STAT)-5b nor drive STAT5b-dependent gene transcription in response to GH (1-100 ng/ml). GHR(H150Q) showed normal affinity for GH but impaired capacity for signal transduction. The compound heterozygote and C94S heterozygote, but not the H150Q heterozygote, showed significant deficiency in activating GH-induced gene expression, corroborating diminished GH-induced STAT5b activation in fibroblasts carrying GHR(C94S) as either a compound heterozygote (in the patients) or a simple heterozygote (in one parent). Conclusions: Each of the compound heterozygous mutations contributed additively to the pathological condition seen in the patients, and the more detrimental of the two mutations, C94S, may cause (partial) primary GHI, even in a heterozygous state.

AB - Context: Primary GH insensitivity (GHI) or Laron syndrome, caused by mutations of the GH receptor (GHR) gene, has a clinical phenotype of postnatal growth failure associated with normal elevated serum concentrations of GH and low serum levels of IGF-I. Objective: We investigated the clinical and biochemical implications of molecular defects in the GHR gene in an Austrian family with two daughters who were GHI. Patients: Patient 1 [height, -4.8 SD score (SDS)] and patient 2 (height, -5.0 SDS) had elevated circulating levels of GH, low-normal levels of GH-binding protein, and abnormally low IGF-I (-5.0 SDS and -2.6 SDS, respectively) and IGF-binding protein-3 (-2.6 SDS and -2.0 SDS, respectively). Results: Both patients carry novel compound, missense, heterozygous GHR mutations, C94S and H150Q. In vitro reconstitution experiments demonstrated that whereas each of the mutants could be stably expressed, GHR(C94S) lost its affinity for GH and could neither activate signal transducer and activator of transcription (STAT)-5b nor drive STAT5b-dependent gene transcription in response to GH (1-100 ng/ml). GHR(H150Q) showed normal affinity for GH but impaired capacity for signal transduction. The compound heterozygote and C94S heterozygote, but not the H150Q heterozygote, showed significant deficiency in activating GH-induced gene expression, corroborating diminished GH-induced STAT5b activation in fibroblasts carrying GHR(C94S) as either a compound heterozygote (in the patients) or a simple heterozygote (in one parent). Conclusions: Each of the compound heterozygous mutations contributed additively to the pathological condition seen in the patients, and the more detrimental of the two mutations, C94S, may cause (partial) primary GHI, even in a heterozygous state.

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