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GHR
growth hormone receptor
The GHR gene provides instructions for the growth hormone receptor, a protein vital for cell growth, division, and metabolism, primarily by interacting with growth hormone. The GHR gene encodes the growth hormone receptor, a protein located on the surface of cells, particularly liver cells.
GHR is located on the short (p) arm of chromosome 5, at band 5p13.1-p12. Arm ratio per GRCh38 - banding schematic.
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Overview
The GHR gene produces the growth hormone receptor, a protein essential for transmitting signals from growth hormone into cells. This receptor is found in the outer membrane of cells throughout the body, with a high concentration in liver cells.
Activation of the growth hormone receptor initiates a signalling cascade that promotes cell growth and division. It also stimulates the production of insulin-like growth factor I (IGF-I), another key hormone involved in growth and metabolic regulation.
What the gene does
The growth hormone receptor protein, encoded by the GHR gene, is embedded within cell membranes and acts as a binding site for growth hormone. Its extracellular region extends outside the cell, specifically designed to bind growth hormone, similar to a lock and key. This binding event triggers signalling through the intracellular region of the receptor, leading to effects within the cell.
Signalling initiated by the GHR protein plays a crucial role in regulating cell growth and division. It also leads to the synthesis of insulin-like growth factor I (IGF-I), predominantly by the liver, which further influences growth and various metabolic pathways, including how the body processes carbohydrates, proteins, and fats.
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Chromosome location
The GHR gene is located on the short arm of chromosome 5, specifically within the 5p13.1-p12 region. It provides the genetic blueprint for a protein composed of 638 amino acids.
Protein structure
The growth hormone receptor protein contains several distinct functional regions and motifs. An important Fibronectin type-III domain is located between amino acids 151-254. A WSXWS motif is found from amino acids 240-244. The region required for ADAM17-mediated proteolysis spans amino acids 260-262. For JAK2 binding, a critical region exists between amino acids 294-379, which includes a Box 1 motif at amino acids 297-305. Additionally, an UbE motif is present from amino acids 340-349, and a disordered region is identified between amino acids 353-391.
Key variants
Genetic changes (variants) within the GHR gene can affect the structure and function of the growth hormone receptor protein. These variants can lead to altered signalling, impacting the body's response to growth hormone. The clinical significance of these variants can range from mild effects to severe conditions.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.192_193del | p.Ser65fs | Pathogenic | ★★☆☆ | Laron-type isolated somatotropin defect |
c.266+83G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.267-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Laron-type isolated somatotropin defect |
c.335G>T | p.Cys112Phe | Pathogenic | ★★☆☆ | Laron-type isolated somatotropin defect |
c.344A>C | p.Asn115Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Laron-type isolated somatotropin defect |
c.440-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Short stature due to partial GHR deficiency |
c.476T>A | p.Leu159Ter | Pathogenic/Likely pathogenic | ★★☆☆ | See cases |
c.508G>C | p.Asp170His | Pathogenic/Likely pathogenic | ★★☆☆ | Monogenic short statue |
c.618+792A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Laron-type isolated somatotropin defect |
c.703C>T | p.Arg235Ter | Pathogenic | ★★☆☆ | Hypercholesterolemia, familial, 1 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the GHR gene are associated with conditions that affect growth and metabolism. One primary condition linked to GHR gene variants is Growth hormone insensitivity (Laron). This condition can result in short stature, distinctive facial features, and other systemic effects.
UK clinical status
The GHR gene is included in several NHS Genomic Medicine Service national panels. It is listed as 'green' on the Developmental Disorders and Genomic Overgrowth (DDG2P) panel, Foetal Anomalies (R21), IUGR and IGF Abnormalities, Monogenic Short Stature (R453), Pituitary Hormone Deficiency (R159), and Skeletal Dysplasia (R104) panels, indicating its recognised clinical importance within the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the GHR gene?
The GHR gene provides instructions for making the growth hormone receptor protein, which binds to growth hormone. This binding initiates signals within cells that are crucial for growth, cell division, and metabolism.
How do GHR gene variants affect health?
Variants in the GHR gene can impair the function of the growth hormone receptor, leading to conditions like Growth hormone insensitivity (Laron). This means the body cannot properly respond to growth hormone, affecting growth and development.
Is the GHR gene part of any NHS genetic testing panels?
Yes, the GHR gene is included in several NHS Genomic Medicine Service panels, including those for Developmental Disorders and Genomic Overgrowth, Foetal Anomalies, Monogenic Short Stature, and Pituitary Hormone Deficiency, indicating its clinical relevance in the UK.
References
- Guevara-Aguirre J, Rosenbloom AL. Obesity, diabetes and cancer: insight into the relationship from a cohort with growth hormone receptor deficiency. Diabetologia. 2015. PMID: 25316432
- Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Science translational medicine. 2011. PMID: 21325617
- Filopanti M, Giavoli C, Grottoli S. The exon 3-deleted growth hormone receptor: molecular and functional characterization and impact on GH/IGF-I axis in physiological and pathological conditions. Journal of endocrinological investigation. 2011. PMID: 22322534
- Brooks AJ, Waters MJ. The growth hormone receptor: mechanism of activation and clinical implications. Nature reviews. Endocrinology. 2010. PMID: 20664532
- Jorge AA, Arnhold IJ. Growth hormone receptor exon 3 isoforms and their implication in growth disorders and treatment. Hormone research. 2009. PMID: 19407498
- Wassenaar MJ, Dekkers OM, Pereira AM. Impact of the exon 3-deleted growth hormone (GH) receptor polymorphism on baseline height and the growth response to recombinant human GH therapy in GH-deficient (GHD) and non-GHD children with short stature: a systematic review and meta-analysis. The Journal of clinical endocrinology and metabolism. 2009. PMID: 19584188
- Wassenaar MJ, Biermasz NR, Pereira AM. The exon-3 deleted growth hormone receptor polymorphism predisposes to long-term complications of acromegaly. The Journal of clinical endocrinology and metabolism. 2009. PMID: 19864451
- Dos Santos C, Essioux L, Teinturier C. A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone. Nature genetics. 2004. PMID: 15208626
- Savage MO, Woods KA, Johnston LB. Defects of the growth hormone receptor and their clinical implications. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 1999. PMID: 10429882
- Amselem S, Duquesnoy P, Attree O. Laron dwarfism and mutations of the growth hormone-receptor gene. The New England journal of medicine. 1989. PMID: 2779634