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J Clin Endocrinol Metab. 2005 Jan;90(1):542-7. Epub 2004 Nov 9.

A novel C-terminal growth hormone receptor (GHR) mutation results in impaired GHR-STAT5 but normal STAT-3 signaling.

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Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Building 10, Suite 9D42, Bethesda, Maryland 20892, USA.


GH insensitivity (GHI) is an autosomal recessive disorder caused by defects in the GH receptor (GHR). In a 17-yr-old female with severe short stature and biochemical features of GHI, sequencing of GHR gene revealed a compound heterozygosity for two novel mutations: C83X and a G deletion at position 1776 (1776del). 1776del is predicted to result in GHR truncation to 581 amino acids with a nonsense sequence of residues 560-581. To clarify the effect of 1776del on GHR function, wild-type GHR, GHR-1776del, and two additional GHR mutants, GHR-L561X (stop codon at site of the 1776del) and GHR-I582X (translation termination in GHR-1776del) were transiently expressed in CHO cells. After incubation with recombinant human GH, GHR-1776del showed lower signal transducer and activator of transcription 5 (STAT5)-mediated transcriptional activation ( approximately 50%, P < 0.05), as well as STAT5 Tyr694 phosphorylation (P < 0.05) compared with wild-type GHR, whereas GHR-L561X and GHR-I582X showed normal STAT5 phosphorylation and transcriptional activity. In contrast, all vectors produced similar effects on STAT3-mediated transcriptional activation. In conclusion, this novel GHR-1776del mutation in a classical GHI patient illustrates an important mechanism of impaired GHR-STAT5 but intact GHR-STAT3 signaling. This effect might result from interference of C-terminal nonsense sequence in mutated GHR with STAT5 docking to upstream tyrosine residues.

[Indexed for MEDLINE]

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