GHR Gene (Growth Hormone Receptor): Function, Mutations, and Related Diseases

The GHR gene encodes the growth hormone receptor, a single-pass transmembrane protein that binds growth hormone (GH) with high affinity. This receptor is a member of the class I cytokine receptor family and is essential for mediating the effects of GH on growth and metabolism. Upon GH binding, the receptor undergoes conformational changes, activating associated JAK2 tyrosine kinase, which then phosphorylates the receptor and downstream signaling molecules, including STAT5, MAPK, and PI3K/AKT pathways. The GHR is expressed in multiple tissues, with the highest levels in the liver, where it stimulates the production of insulin-like growth factor 1 (IGF-1), the primary mediator of growth-promoting actions. Alternative splicing of the GHR gene produces soluble isoforms, including the growth hormone binding protein (GHBP), which modulates GH bioavailability. Mutations in GHR can lead to growth hormone insensitivity (Laron syndrome), while polymorphisms are associated with variations in growth, metabolic traits, and cancer susceptibility.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• JAK-STAT signaling pathway

• Growth hormone signaling pathway

• PI3K-Akt signaling pathway

• MAPK/ERK signaling pathway

• IGF-1 receptor signaling pathway

The growth hormone receptor (GHR) is a 620-amino acid single-pass transmembrane protein with a large extracellular domain (246 aa) that binds growth hormone, a single transmembrane domain, and an intracellular domain (350 aa) that mediates signal transduction. The receptor exists as a preformed dimer on the cell surface. GH binding induces a conformational change, bringing the two intracellular domains into proximity, which allows JAK2 (Janus kinase 2) to transphosphorylate and activate. Activated JAK2 then phosphorylates tyrosine residues on the GHR, creating docking sites for SH2 domain-containing proteins, primarily STAT5a/b. Phosphorylated STAT5 translocates to the nucleus to regulate gene transcription, including IGF-1. The receptor also activates other pathways, including MAPK and PI3K/AKT. The soluble GHBP is produced by proteolytic cleavage of the membrane-bound receptor and acts as a carrier protein for GH in the circulation, modulating its half-life and tissue availability.