GHR (growth hormone receptor; HGNC:4263, NCBI Gene ID 2690) is a human locus mapped to chromosome band 5p13.1-p12 that encodes single-pass transmembrane Growth Hormone Receptor (620 mature aa) & cleaved plasma GH-binding protein (GHBP). GHR acts in GH1-GHR-JAK2-STAT5B-SOCS2 somatotropic signaling cascade, together with Growth Hormone Receptor Overview, GH1 (Pituitary Growth Hormone 1 Gene), and IGF1 (Insulin-Like Growth Factor 1 Gene). Encodes the transmembrane growth hormone receptor; biallelic loss-of-function causes Laron syndrome with severe dwarfism and protection from diabetes and cancer.
Biallelic LoF causes Laron syndrome (GH insensitivity with ultra-low cancer/T2D incidence); target of pegvisomant in acromegaly
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 10-exon gene spanning ~300 kb on chromosome 5p13.1-p12 (with multiple alternative 5-prime non-coding exons and a common anthropomorphic polymorphic deletion of coding exon 3, GHRd3), encoding a 638-residue preprotein (620 mature aa) whose extracellular fibronectin-III-like domain can be proteolytically shed by ADAM17 (TACE) to circulate as growth hormone-binding protein (GHBP).
Cellular & Tissue Expression Profile: Expressed at highest density on hepatic hepatocytes, epiphyseal growth plate chondrocytes, osteoblasts, skeletal muscle fibers, and white adipocytes.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Exists on the plasma membrane as a preformed homodimer whose cytoplasmic Box 1 proline-rich motif constitutively binds Janus kinase 2 (JAK2); asymmetric 1:2 binding of a single GH1 molecule rotates the juxtamembrane helices to trans-activate JAK2, which phosphorylates GHR cytoplasmic tyrosines to recruit STAT5B (driving IGF1, IGFBP3, and negative-feedback SOCS2 transcription), STAT1/3, and IRS-PI3K signaling.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Biallelic loss-of-function mutations (such as the Ecuadorian founder splice mutation p.Glu180splice in exon 6) cause autosomal recessive Laron syndrome (primary growth hormone insensitivity), characterized by severe postnatal dwarfism, elevated circulating pituitary GH, and extremely low serum IGF-1; longitudinal cohort studies of Ecuadorian Laron homozygotes revealed enhanced insulin sensitivity and near-complete absence of type 2 diabetes and lethal malignancies.
Therapeutic & Clinical Pharmacology: Pharmacologically blocked by the FDA-approved engineered GH analog pegvisomant (Somavert, which binds Site 1 with high affinity but carries a Gly120Lys substitution at Site 2 that prevents functional GHR dimer rotation) to normalize IGF-1 in acromegaly, while Laron syndrome is bypassed downstream with recombinant IGF-1 (mecasermin).