Deletions/mutations cause Isolated Growth Hormone Deficiency (IGHD IA–III); treated by somatropin & long-acting lonapegsomatropin/somapacitan
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 5-exon gene situated at the 5-prime end of the 66 kb five-gene growth hormone/chorionic somatomammotropin cluster on chromosome 17q23.3 (GH1, CSHP1, CSH1, GH2, CSH2), controlled by the pituitary-specific transcription factor POU1F1 (PIT-1) and undergoing alternative splicing in ~10% of transcripts at exon 3 to yield a 20 kDa isoform alongside the major 191-residue 22 kDa four-helix-bundle protein.
Cellular & Tissue Expression Profile: Synthesized, stored in dense secretory granules, and secreted in nocturnal slow-wave-sleep-entrained pulses exclusively by acidophilic somatotroph cells of the anterior pituitary gland under dual hypothalamic control (stimulated by GHRH and gastric ghrelin; inhibited by somatostatin).
Molecular Function & Pathways
Biochemical & Physiological Mechanism: A single asymmetric GH1 molecule sequentially binds two identical cell-surface Growth Hormone Receptors (GHR) via distinct high-affinity Site 1 and lower-affinity Site 2 interfaces, inducing a rotational conformational change in the pre-dimerized GHR transmembrane helices that activates associated JAK2 tyrosine kinases and STAT5B to drive hepatic transcription of IGF1, IGFBP3, and IGFALS while acutely stimulating hormone-sensitive lipase in adipose tissue.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Homozygous gene deletions (6.7 kb or 7.6 kb unequal crossover deletions within the 17q23.3 cluster) cause autosomal recessive Isolated Growth Hormone Deficiency Type IA (with anti-GH antibodies upon therapy), biallelic nonsense/frameshift mutations cause IGHD IB, and dominant-negative exon 3 skipping mutations (which trap wild-type GH in the endoplasmic reticulum and trigger somatotroph apoptosis) cause autosomal dominant IGHD Type II.
Therapeutic & Clinical Pharmacology: Treated with recombinant human growth hormone (somatropin, one of the earliest recombinant DNA medicines) and weekly long-acting prodrugs (lonapegsomatropin, somapacitan, somatrogon), whereas GH-excess acromegaly from somatotroph adenomas is treated with the Site-2-mutated GHR antagonist pegvisomant.