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

Division of Clinical Sciences (North) (A.M., M.M., I.R.W., R.J.M.R.), University of Sheffield, Sheffield S5 7AU, United Kingdom; Department of Endocrinology (L.M., C.C.-H., M.O.S., A.J.L.C.), Barts & the London, Queen Mary University of London, London EC1A 7BE, United Kingdom; Hospital Sant Pau (M.J.B., S.M.W.), Autonomous University of Barcelona, Spain; and Department of Medicine (C.M.B.), Ludwig-Maximilians University, Munich 80336, Germany

Address all correspondence and requests for reprints to: Professor Richard J. M. Ross, Clinical Sciences, Northern General Hospital, Sheffield, S5 7AU, United Kingdom. E-mail: r.j.ross{at}sheffield.ac.uk.

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.

This work was supported by Novo Nordisk (to M.M.).

A.M. and L.M. contributed equally to this work.

Abbreviations: CHO, Chinese hamster ovary; GHBP, GH binding protein; GHIS, GH insensitivity syndrome; GHR, GH receptor; GHRwt, wild-type GHR; hGH, human GH; IGFBP, IGF binding protein; Jak, Janus kinase; N, normal range; SDS, SD score; Stat, signal transducer and activator of transcription.

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