Growth Hormone (GH) Insensitivity Syndrome due to a GH Receptor Truncated after Box1, Resulting in Isolated Failure of STAT 5 Signal Transduction

• Published in: The journal of clinical endocrinology and metabolism 2004-03, Vol.89 (3), p.1259-1266
• Main Authors: Milward, A., Metherell, L., Maamra, M., Barahona, M. J., Wilkinson, I. R., Camacho-Hübner, C., Savage, M. O., Bidlingmaier, C. M., Clark, A. J. L., Ross, R. J. M., Webb, S. M.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Biological and medical sciences; DNA-Binding Proteins - metabolism; Endocrinopathies; Female; Fundamental and applied biological sciences. Psychology; Human Growth Hormone - metabolism; Humans; Male; MAP Kinase Signaling System - physiology; Medical sciences; Middle Aged; Milk Proteins; Molecular Sequence Data; Phenotype; Prolactin - metabolism; Protein Binding; Receptors, Somatotropin - genetics; Receptors, Somatotropin - metabolism; STAT3 Transcription Factor; STAT5 Transcription Factor; Trans-Activators - metabolism; Vertebrates: endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2003-031418

Congenital GH insensitivity syndrome (GHIS) is usually the result of a mutation in the extracellular domain of the GH receptor (GHR). We report one of only a small number of mutations so far identified within the intracellular domain of the GHR. The probands are a 53-yr-old woman, height 114 cm (sd score, −8.7), peak GH 45 μg/liter during hypoglycemia, IGF-I 8.0 μg/liter [normal range (N) N 54–389], IGF binding protein-3 16 nmol/liter (N 61–254), GHBP 6.8% (N > 10); and her 57-yr-old brother, height 140 cm (sd score, −6), IGF-I 38.8 μg/liter (N 54–290), IGF binding protein-3 30 nmol/liter (N 61–196). Both patients were homozygous for a 22-bp deletion in the DNA encoding the cytoplasmic domain of the GHR, resulting in a frameshift and premature stop codon. The resultant GHR is truncated at amino acid 449 (GHR1–449) after Box1, the Janus kinase 2 binding domain of the receptor. Functional studies in HEK293 and Chinese hamster ovary cells show GHR1–449 to have a cellular distribution similar to that of the wild-type GHR, judged by binding of iodinated GH, FACS analysis, and immunocytochemistry. Western blot analysis showed GH-induced phosphorylation of Janus kinase 2, signal transducer and activator of transcription (Stat)3, and Erk2 for both GHR1–449 and wild-type GHR. However, no Stat5 activity was detected in cells expressing GHR1–449, consistent with the fact that GHR1–449 contains no Stat5 binding site. In conclusion, we report two adult siblings with GHIS due to a mutation in the intracellular domain of GHR resulting in a selective loss of Stat5 signaling. Results are consistent with the hypothesis that the loss of signaling through the Stat5 pathway results in GHIS.