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ADA
adenosine deaminase
The ADA gene provides instructions for creating adenosine deaminase, an enzyme critical for healthy immune system function and the proper breakdown of cellular waste products. The ADA gene codes for the adenosine deaminase enzyme, which plays a vital role in purine metabolism by converting deoxyadenosine into deoxyinosine.
ADA is located on the long (q) arm of chromosome 20, at band 20q13.12. Arm ratio per GRCh38 - banding schematic.
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Overview
The ADA gene, or adenosine deaminase gene, is fundamental for maintaining immune system health. It encodes the adenosine deaminase enzyme, which is expressed in all human cells, though its concentrations are highest within lymphocytes- specialised white blood cells crucial for defending the body against pathogens.
Dysfunction of the ADA gene is primarily associated with Severe Combined Immunodeficiency (SCID) due to adenosine deaminase deficiency, a severe genetic disorder characterised by profound immune system impairment.
What the gene does
The adenosine deaminase enzyme, produced from the ADA gene, is central to the purine salvage pathway, a metabolic process for recycling purine bases. Its main function involves the conversion of deoxyadenosine to deoxyinosine. Deoxyadenosine is a byproduct generated during the natural breakdown of DNA within cells.
Without functional adenosine deaminase, deoxyadenosine can accumulate to toxic levels, particularly within lymphocytes. This buildup is harmful because deoxyadenosine and its derivatives can inhibit DNA synthesis and repair, leading to the premature death of these critical immune cells. Consequently, the enzyme's proper activity is indispensable for the normal development and function of the immune system, particularly in lymphoid tissues like the thymus and lymph nodes.
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Chromosome location
The ADA gene is located on chromosome 20, specifically at position 20q13.12. This chromosomal location indicates its precise address within the human genome, where it resides among other genes responsible for various cellular functions.
Protein structure
The adenosine deaminase protein is composed of 363 amino acids. A specific region within the protein, spanning amino acids 126-143, is required for its interaction with DDP4 (dipeptidyl peptidase-4), indicating a potential role in cellular signalling or enzyme regulation.
Key variants
Variants within the ADA gene can lead to alterations in the structure or function of the adenosine deaminase enzyme. Many identified variants involve single amino acid changes, which can significantly reduce or eliminate the enzyme's activity. The consequences of these genetic changes can range from mild effects to severe immune deficiencies, depending on the specific variant and its impact 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.396dup | p.Val133fs | Pathogenic | ★★★☆ | Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency |
c.532del | p.Val177_Val178insTer | Pathogenic | ★★★☆ | Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency |
c.603C>G | p.Tyr201Ter | Pathogenic | ★★★☆ | Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency |
c.632G>A | p.Arg211His | Pathogenic | ★★★☆ | Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency |
c.646G>A | p.Gly216Arg | Pathogenic | ★★★☆ | Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency |
c.716G>A | p.Gly239Asp | Pathogenic | ★★★☆ | Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency |
c.736C>T | p.Gln246Ter | Pathogenic | ★★★☆ | Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency |
c.845G>A | p.Arg282Gln | Pathogenic | ★★★☆ | Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency |
c.975+1G>A | - | Pathogenic | ★★★☆ | Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency |
c.976-1G>C | - | Pathogenic | ★★★☆ | Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase 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 ADA gene are primarily associated with a condition known as Severe Combined Immunodeficiency (SCID) due to ADA deficiency. This inherited disorder severely compromises the immune system, typically presenting with health problems early in life. Affected individuals are highly susceptible to recurrent, severe infections due to a profound deficiency of functional lymphocytes.
- SCID (ADA deficiency) Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic ADA 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 ADA gene is recognised within the UK's genomic healthcare system and is included in several NHS England Genomic Medicine Service clinical panels. These panels cover various conditions, including COVID-19 research, DDG2P, Infantile enterocolitis & monogenic inflammatory bowel disease, Likely inborn error of metabolism, Primary immunodeficiency or monogenic inflammatory bowel disease, Severe combined immunodeficiency with adenosine deaminase deficiency, and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ADA gene?
The ADA gene provides instructions for creating the adenosine deaminase enzyme, which is crucial for breaking down deoxyadenosine, a toxic byproduct of DNA breakdown. This process is essential for maintaining a healthy immune system.
Which condition is most commonly associated with ADA gene variants?
Variants in the ADA gene are most commonly associated with Severe Combined Immunodeficiency (SCID) due to ADA deficiency. This condition severely impairs the immune system, making individuals vulnerable to severe infections.
Why is the adenosine deaminase enzyme important for the immune system?
The adenosine deaminase enzyme prevents the build-up of toxic deoxyadenosine, particularly in immune cells called lymphocytes. High levels of deoxyadenosine can lead to the death of these cells, compromising the body's ability to fight off infections.
References
- Blackburn MR, Thompson LF. Adenosine deaminase deficiency: unanticipated benefits from the study of a rare immunodeficiency. Journal of immunology (Baltimore, Md. : 1950). 2012. PMID: 22262755
- Hershfield MS. New insights into adenosine-receptor-mediated immunosuppression and the role of adenosine in causing the immunodeficiency associated with adenosine deaminase deficiency. European journal of immunology. 2005. PMID: 15580654
- Nyhan WL. Disorders of purine and pyrimidine metabolism. Molecular genetics and metabolism. 2005. PMID: 16176880
- Hershfield MS. Genotype is an important determinant of phenotype in adenosine deaminase deficiency. Current opinion in immunology. 2003. PMID: 14499267