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JAK3
Janus kinase 3
The JAK3 gene provides instructions for a protein critical to immune system development and function, particularly in regulating specific white blood cells. JAK3 encodes Janus kinase 3, an enzyme that plays a vital role in immune responses.
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 is fundamental for the normal development and operation of the immune system. The protein it produces is a key component in a critical cellular communication system, influencing the growth and maturation of various immune cells.
Disruptions in the JAK3 gene can lead to conditions that severely impair the immune system, making individuals highly susceptible to infections.
What the gene does
The JAK3 protein is an integral part of the JAK/STAT signalling pathway, which transmits chemical signals from outside the cell to the cell's nucleus. This pathway is crucial for regulating the growth and maturation of specific types of white blood cells, including T cells, B cells, and natural killer cells. These lymphocytes are vital for identifying and eliminating bacteria, viruses, and fungi, and for orchestrating the overall immune response. The JAK3 protein helps relay these signals, ensuring immune cells develop and function correctly.
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Chromosome location
The JAK3 gene is located on chromosome 19, specifically at position 13.11 on the short (p) arm, denoted as 19p13.11.
Protein structure
The JAK3 protein consists of 1124 amino acids and features several distinct functional regions. It includes a region involved in interaction with cytokine, interferon, and growth hormone receptors (amino acids 1-223). There is also a FERM domain (amino acids 24-356) and an atypical SH2 domain (amino acids 375-475). Additionally, the protein contains two protein kinase domains, Protein kinase 1 (amino acids 521-781) and Protein kinase 2 (amino acids 822-1111), which are essential for its enzymatic activity.
Key variants
Variants within the JAK3 gene can disrupt the normal production or function of the Janus kinase 3 protein. These genetic changes can lead to a protein that is unstable, quickly broken down, or entirely absent, thereby impairing its crucial role in immune system signalling.
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.2350G>A | p.Asp784Asn | 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 | ★★☆☆ | JAK3-related disorder |
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 |
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). This condition is characterised by a severely compromised immune system, leading to recurrent and persistent infections that can be life-threatening. More than 50 JAK3 gene mutations have been identified in people with this form of SCID. Most of these genetic changes prevent the production of the JAK3 protein entirely.
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 part of several diagnostic panels in the UK, as listed on NHS England's PanelApp. It is included in the COVID-19 research panel, the DDG2P panel, and the Primary immunodeficiency or monogenic inflammatory bowel disease panel (R15).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the JAK3 gene do?
The JAK3 gene provides instructions for making the Janus kinase 3 protein, which is vital for the normal development and function of the immune system. It plays a key role in the JAK/STAT signalling pathway, helping to regulate the growth and maturation of important white blood cells like T cells, B cells, and natural killer cells.
What is JAK3-deficient severe combined immunodeficiency (SCID)?
JAK3-deficient SCID is a severe inherited immune disorder caused by pathogenic variants in the JAK3 gene. It results in a highly compromised immune system, making individuals extremely vulnerable to severe and persistent infections that can be life-threatening.
How is JAK3-related SCID inherited?
JAK3-deficient severe combined immunodeficiency (SCID) is inherited in an autosomal recessive pattern. This means an individual must inherit two copies of the altered gene (one from each parent) to develop the condition. Parents who carry one copy of the altered gene typically do not show symptoms.
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