Growth hormone (GH) insensitivity syndrome due to a GH receptor truncated after Box1, resulting in isolated failure of STAT 5 signal transduction

A. Milward, L. Metherell, M. Maamra, M. J. Barahona, I. R. Wilkinson, C. Camacho-Hübner, M. O. Savage, C. M. Bidlingmaier, A. J.L. Clark, R. J.M. Ross, S. M. Webb

Research output: Contribution to journalArticleResearchpeer-review

57 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)1259-1266
JournalJournal of Clinical Endocrinology and Metabolism
Volume89
Issue number3
DOIs
Publication statusPublished - 1 Mar 2004

Fingerprint

Dive into the research topics of 'Growth hormone (GH) insensitivity syndrome due to a GH receptor truncated after Box1, resulting in isolated failure of STAT 5 signal transduction'. Together they form a unique fingerprint.

Cite this