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We have previously reported a novel heterozygous donor splice site mutation in intron 9 of the GH receptor (GHR) gene in Japanese siblings who showed partial GH insensitivity and high serum GH-binding protein (GHBP) levels. This mutation caused the splicing abnormality and produced the truncated GHR consisting of 277 amino acids (GHR-277), which lacked most of the intracellular domain of GHR, including both boxes 1 and 2. In this study, we have characterized the function of GHR-277 expression in COS-7 and CHO cells in vitro. Scatchard analysis revealed that GHR-277 possessed approximately 1.5 times higher affinity to GH and twice the number of binding sites compared to wild-type full-length GHR (GHR-fl). The GHBP level in culture medium of GHR-277-expressing cells was approximately 3 times higher than that in GHR-fl-expressing cells. Interestingly, the ligand-induced internalization of GHR-277 was significantly reduced compared with that of GHR-fl. Moreover, in GH-induced tyrosine phosphorylation of signal transducer and activator of transcription-5 (STAT5), GHR-277 exerted a dominant negative effect when GHR-277 and GHR-fl were cotransfected. These in vitro data would well explain the clinical characteristics in our patients showing high serum GHBP levels and development of short stature despite a heterozygous mutation of the GHR gene.

the journal of clinical endocrinology and metabolism/journal of clinical endocrinology and metabolism

Functional Characterization of Truncated Growth Hormone (GH) Receptor-(1–277) Causing Partial GH Insensitivity Syndrome with High GH-Binding Protein<sup>1</sup>

Functional Characterization of Truncated Growth Hormone (GH) Receptor-(1–277) Causing Partial GH Insensitivity Syndrome with High GH-Binding Protein1

Functional Characterization of Truncated Growth Hormone (GH) Receptor-(1–277) Causing Partial GH Insensitivity Syndrome with High GH-Binding Protein¹