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
| Autor: | Vivian Hwa, Peng Fang, Herwig Frisch, Brian M. Little, Serge Amselem, Ron G. Rosenfeld, Gabriele Haeusler, Stefan Riedl, Katherine L. Pratt |
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| Rok vydání: | 2007 |
| Předmět: |
Heterozygote
medicine.medical_specialty Transcription Genetic Endocrinology Diabetes and Metabolism medicine.medical_treatment DNA Mutational Analysis Clinical Biochemistry Mutant Gene Dosage Mutation Missense Growth hormone receptor Biology Compound heterozygosity Biochemistry Insulin-like growth factor Endocrinology Internal medicine STAT5 Transcription Factor medicine Laron syndrome Humans Missense mutation Insulin-Like Growth Factor I Child Cells Cultured Family Health Human Growth Hormone Biochemistry (medical) Infant Newborn Infant Heterozygote advantage Receptors Somatotropin Fibroblasts medicine.disease Laron Syndrome Somatropin Female |
| Zdroj: | The Journal of Clinical Endocrinology & Metabolism. 92:2223-2231 |
| ISSN: | 1945-7197 0021-972X |
| DOI: | 10.1210/jc.2006-2624 |
| Popis: | 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.We investigated the clinical and biochemical implications of molecular defects in the GHR gene in an Austrian family with two daughters who were GHI.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).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).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. |
| Databáze: | OpenAIRE |
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