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INSR
insulin receptor
The INSR gene encodes the insulin receptor, a vital protein found on cell surfaces that binds to insulin and plays a central role in regulating blood glucose levels and cellular metabolism. The INSR gene is fundamental for proper metabolic function.
INSR is located on the short (p) arm of chromosome 19, at band 19p13.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The INSR gene provides the blueprint for the insulin receptor, a protein critical for the body's response to insulin. This receptor is found on the surface of many cell types and is essential for metabolic processes, particularly glucose homeostasis. When insulin binds to its receptor, it triggers a cascade of intracellular signals that enable cells to absorb glucose from the bloodstream for energy or storage.
Genetic changes in the INSR gene can impair the function of the insulin receptor, leading to conditions where the body's cells do not respond effectively to insulin. These conditions are broadly categorised as severe insulin resistance syndromes, which can have varying degrees of clinical severity and impact multiple organ systems.
What the gene does
The INSR gene directs the synthesis of the insulin receptor protein. This receptor is initially produced as a single polypeptide chain that undergoes processing to form a functional receptor composed of two alpha and two beta subunits. The alpha subunits are positioned on the cell's exterior and are responsible for binding to insulin circulating in the blood. The beta subunits span the cell membrane, with portions extending into the cell's interior.
Upon insulin binding to the alpha subunits, a conformational change is induced that activates the tyrosine kinase activity of the beta subunits. This activation initiates intracellular signalling pathways, including those involving PIK3R1-binding and interactions with proteins like IRS1, SHC1, and STAT5B. These pathways orchestrate various cellular functions, most notably regulating glucose uptake, metabolism, cell growth, and differentiation. Proper receptor function ensures cells effectively respond to insulin's signals.
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Chromosome location
The INSR gene is located on chromosome 19, specifically at the band 19p13.2. This genomic position indicates its precise address within the human genome. The gene's location is consistent across individuals and is a key identifier for genetic studies and diagnostic purposes.
Protein structure
The insulin receptor protein is a complex structure consisting of 1382 amino acids. Key functional regions include three Fibronectin type-III domains: Fibronectin type-III 1 (amino acids 624-726), Fibronectin type-III 2 (amino acids 757-842), and Fibronectin type-III 3 (amino acids 853-947). The protein also contains specific regions for insulin binding (amino acids 733-741) and a crucial Protein kinase domain (amino acids 1023-1298) responsible for initiating intracellular signalling. Other notable regions include binding sites important for interaction with IRS1, SHC1 and STAT5B (amino acid 999), and a PIK3R1-binding region (amino acids 1361-1364). Several Disordered regions are also present throughout the protein, for example, from amino acids 686-708, 746-766, and 1360-1382.
Key variants
Genetic variations within the INSR gene can range from single nucleotide changes to larger deletions or duplications. These variants can alter the structure or function of the insulin receptor protein, affecting its ability to bind insulin or transmit signals effectively. The inheritance pattern for conditions associated with INSR variants can be autosomal dominant (AD) or autosomal recessive (AR), depending on the specific variant and its effect on protein function.
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.1610+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Leprechaunism syndrome |
c.3058C>T | p.Arg1020Ter | Pathogenic | ★★☆☆ | Hyperinsulinism due to INSR deficiency |
c.3079C>T | p.Arg1027Ter | Pathogenic | ★★☆☆ | INSR-related disorder |
c.3602G>A | p.Arg1201Gln | Pathogenic | ★★☆☆ | INSR-related disorder |
c.707A>G | p.His236Arg | Pathogenic/Likely pathogenic | ★★☆☆ | INSR-related disorder |
c.1894_1895insTTAA | p.Ser632fs | Pathogenic | ★☆☆☆ | Insulin resistance |
c.1976G>A | p.Trp659Ter | Pathogenic | ★☆☆☆ | Lipodystrophy - childhood onset |
c.2164G>T | p.Glu722Ter | Pathogenic | ★☆☆☆ | not provided |
c.2437C>T | p.Arg813Ter | Pathogenic | ★☆☆☆ | not provided |
c.3196C>T | p.Arg1066Ter | Pathogenic | ★☆☆☆ | Hyperinsulinism due to INSR deficiency |
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 INSR gene are primarily associated with a spectrum of severe insulin resistance syndromes. These include conditions such as Donohue syndrome, Rabson-Mendenhall syndrome, and type A insulin resistance syndrome, which vary in their severity and clinical presentation. Insulin resistance means the body's cells do not respond appropriately to insulin, leading to impaired glucose metabolism and diverse symptoms. INSR variants are also implicated in polycystic ovary syndrome.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic INSR variants typically follow autosomal dominant or autosomal recessive inheritance.
Carrier frequency by population How common is heterozygous INSR carrier status across ancestry groups?UK clinical status
The INSR gene is recognised within the NHS Genomic Medicine Service due to its association with several conditions. It is listed as a 'green' gene on multiple NHS England National Genomic Test Directory panels, indicating strong evidence for its role in disease. These panels include Congenital hyperinsulinism, Diabetes with additional phenotypes suggestive of a monogenic aetiology, Familial diabetes, Foetal anomalies, Insulin resistance (including lipodystrophy), IUGR and IGF abnormalities, Monogenic diabetes, Neonatal diabetes, and Severe insulin resistance and lipodystrophy syndromes.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the INSR gene?
The INSR gene provides instructions for making the insulin receptor protein. This receptor is crucial for binding insulin and initiating the cellular processes that regulate blood glucose levels and overall metabolism.
What happens if the INSR gene doesn't work correctly?
If the INSR gene does not function properly, the insulin receptor may be impaired. This can lead to insulin resistance, where the body's cells do not respond effectively to insulin, causing conditions such as severe insulin resistance syndromes.
How can INSR gene variants affect health?
Variants in the INSR gene can alter how the insulin receptor functions, leading to a spectrum of health issues primarily related to impaired glucose metabolism. These can range from severe conditions like Donohue syndrome to milder forms of insulin resistance and polycystic ovary syndrome.
References
- Hubbard SR. The insulin receptor: both a prototypical and atypical receptor tyrosine kinase. Cold Spring Harbor perspectives in biology. 2013. PMID: 23457259
- Grasso V, Colombo C, Favalli V. Six cases with severe insulin resistance (SIR) associated with mutations of insulin receptor: Is a Bartter-like syndrome a feature of congenital SIR? Acta diabetologica. 2013. PMID: 23824322
- Semple RK, Savage DB, Cochran EK. Genetic syndromes of severe insulin resistance. Endocrine reviews. 2011. PMID: 21536711
- Maassen JA, Tobias ES, Kayserilli H. Identification and functional assessment of novel and known insulin receptor mutations in five patients with syndromes of severe insulin resistance. The Journal of clinical endocrinology and metabolism. 2003. PMID: 12970295
- Longo N, Wang Y, Smith SA. Genotype-phenotype correlation in inherited severe insulin resistance. Human molecular genetics. 2002. PMID: 12023989