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JAK3
Janus kinase 3
The JAK3 gene provides the blueprint for a protein vital for the healthy development and operation of the human immune system. JAK3 plays a vital role in immune cell signalling, particularly for T cells, B cells, and natural killer cells.
JAK3 is located on the short (p) arm of chromosome 19, at band 19p13.11. Arm ratio per GRCh38 - banding schematic.
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Overview
The Janus kinase 3 (JAK3) gene encodes a protein that is fundamental for a healthy immune system. This protein is involved in transmitting signals within cells, regulating the growth and maturation of various white blood cells, including T cells, B cells, and natural killer cells. These immune cells are essential for defending the body against infections from bacteria, viruses, and fungi.
Defects in the JAK3 gene can lead to compromised immune function, making individuals highly susceptible to severe and recurrent infections.
What the gene does
The JAK3 protein is an integral component of the JAK/STAT signalling pathway, a crucial system that relays chemical signals from the cell's exterior to its nucleus. This pathway is critical for orchestrating immune responses and cell development. Within this process, the JAK3 protein governs the growth and maturation of specific white blood cells, such as T cells and natural killer cells, which are key players in cellular immunity. It also contributes to the normal maturation of B cells, which are responsible for producing antibodies.
The JAK3 protein's structure facilitates its function. An N-terminal region spanning amino acids 1-223 is involved in interaction with cytokine, interferon, and growth hormone receptors. The FERM domain (amino acids 24-356) and an atypical SH2 domain (amino acids 375-475) are important for protein-protein interactions and signal transduction. The catalytic activity is provided by two protein kinase domains: Protein kinase 1 (amino acids 521-781) and Protein kinase 2 (amino acids 822-1111), which enable the phosphorylation of target proteins to propagate signals.
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Chromosome location
The JAK3 gene is situated on chromosome 19, specifically at position 19p13.11. This gene spans a region of the short (p) arm of chromosome 19. The protein it encodes is composed of 1124 amino acids.
Protein structure
The JAK3 protein, comprising 1124 amino acids, possesses a modular structure with several distinct functional domains. The N-terminal region, spanning amino acids 1-223, facilitates interaction with cytokine, interferon, and growth hormone receptors. Following this, the FERM domain (amino acids 24-356) and an atypical SH2 domain (amino acids 375-475) are crucial for protein binding and signal relay. The protein's kinase activity is mediated by two key catalytic regions: Protein kinase 1 (amino acids 521-781) and Protein kinase 2 (amino acids 822-1111).
Key variants
Variants within the JAK3 gene can disrupt its normal function, leading to impaired immune system development and activity. Most identified pathogenic variants prevent the production of a functional JAK3 protein or result in a protein that is unstable and quickly degraded. These genetic changes can significantly impact cellular signalling pathways essential for immune cell maturation and response.
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.1333C>T | p.Arg445Ter | Pathogenic | ★★★☆ | T-B+ severe combined immunodeficiency due to JAK3 deficiency |
c.1351C>T | p.Arg451Ter | Pathogenic | ★★★☆ | T-B+ severe combined immunodeficiency due to JAK3 deficiency |
c.1695C>A | p.Cys565Ter | Pathogenic | ★★★☆ | T-B+ severe combined immunodeficiency due to JAK3 deficiency |
c.1837C>T | p.Arg613Ter | Pathogenic | ★★★☆ | T-B+ severe combined immunodeficiency due to JAK3 deficiency |
c.2311C>T | p.Arg771Ter | Pathogenic | ★★★☆ | T-B+ severe combined immunodeficiency due to JAK3 deficiency |
c.678_679del | p.Cys227fs | Pathogenic | ★★★☆ | T-B+ severe combined immunodeficiency due to JAK3 deficiency |
c.1476del | p.His492fs | Pathogenic/Likely pathogenic | ★★☆☆ | T-B+ severe combined immunodeficiency due to JAK3 deficiency |
c.1951C>T | p.Arg651Trp | Pathogenic/Likely pathogenic | ★★☆☆ | T-B+ severe combined immunodeficiency due to JAK3 deficiency |
c.2712C>A | p.Tyr904Ter | Pathogenic | ★★☆☆ | T-B+ severe combined immunodeficiency due to JAK3 deficiency |
c.2817C>A | p.Tyr939Ter | Pathogenic/Likely pathogenic | ★★☆☆ | T-B+ severe combined immunodeficiency due to JAK3 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
Pathogenic variants in the JAK3 gene are primarily associated with JAK3-deficient severe combined immunodeficiency (SCID). More than 50 such mutations have been identified. This is a severe inherited condition characterised by a profound impairment of the immune system. Individuals with JAK3-deficient SCID experience recurrent and persistent infections that can be life-threatening due to their inability to mount an effective immune response.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic JAK3 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The JAK3 gene is included in several UK NHS national genomic testing panels. It is recognised in the COVID-19 research panel, the Deciphering Developmental Disorders (DDG2P) panel, and the Primary immunodeficiency or monogenic inflammatory bowel disease (R15) panel. Its presence on these panels highlights its clinical significance within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the JAK3 gene?
The JAK3 gene provides instructions for creating a protein essential for the normal development and function of the immune system, particularly for immune cell signalling and the maturation of T cells, B cells, and natural killer cells.
What condition is most commonly associated with JAK3 gene variants?
Variants in the JAK3 gene are most commonly associated with JAK3-deficient severe combined immunodeficiency (SCID), a severe immune disorder that leads to recurrent and potentially life-threatening infections.
How does the JAK3 protein contribute to immune response?
The JAK3 protein is part of the JAK/STAT signalling pathway, which transmits signals within cells. These signals regulate the growth, maturation, and activation of key immune cells like T cells, B cells, and natural killer cells, enabling the body to fight off infections.
References
- Pesu M, Candotti F, Husa M. Jak3, severe combined immunodeficiency, and a new class of immunosuppressive drugs. Immunological reviews. 2005. PMID: 15661026
- O'Shea JJ, Husa M, Li D. Jak3 and the pathogenesis of severe combined immunodeficiency. Molecular immunology. 2004. PMID: 15220007
- Notarangelo LD, Mella P, Jones A. Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency. Human mutation. 2001. PMID: 11668610
- Vihinen M, Villa A, Mella P. Molecular modeling of the Jak3 kinase domains and structural basis for severe combined immunodeficiency. Clinical immunology (Orlando, Fla.). 2000. PMID: 10900158