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ADA
adenosine deaminase
The ADA gene provides instructions for producing the adenosine deaminase enzyme, which is crucial for immune system function and preventing the build-up of harmful molecules. The ADA gene encodes the adenosine deaminase enzyme, found in all cells but particularly abundant in immune cells called lymphocytes.
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, is essential for normal cellular function, particularly within the immune system. It directs the production of an enzyme that helps to process a specific molecule, preventing its accumulation to harmful levels. Dysregulation of this gene is linked to severe health conditions, primarily affecting immune development and function.
What the gene does
The adenosine deaminase enzyme, encoded by the ADA gene, is responsible for converting deoxyadenosine into deoxyinosine. Deoxyadenosine is a molecule that accumulates when DNA is broken down and can be toxic to cells, especially lymphocytes. Lymphocytes are specialised immune cells found in lymphoid tissues, such as the thymus and lymph nodes, which are critical for defending the body against pathogens like viruses and bacteria. By neutralising deoxyadenosine, the ADA enzyme prevents its build-up, which could otherwise lead to early cell death and severely impair immune system development and function. Although present in all cells, the enzyme is found in the highest concentrations within lymphocytes, underscoring its importance for immune health.
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Chromosome location
The ADA gene is situated on chromosome 20 at position q13.12. This specific genomic location indicates its address within the long arm of chromosome 20, providing a precise reference point for genetic studies and clinical investigations.
Protein structure
The adenosine deaminase protein consists of 363 amino acids. A specific region spanning amino acids 126-143 has been identified as required for binding to DDP4, suggesting a role in protein-protein interactions or enzymatic regulation.
Key variants
Variants within the ADA gene encompass a range of changes that can affect the function or production of the adenosine deaminase enzyme. These genetic alterations can include single nucleotide changes, insertions, or deletions, potentially leading to a dysfunctional or absent protein. Such changes can disrupt the enzyme's ability to process deoxyadenosine, leading to its accumulation and subsequent cellular toxicity.
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 SCID (ADA deficiency). This condition significantly impairs the immune system and typically presents with severe health problems early in life. Most ADA gene variants linked to SCID involve changes to single amino acids within the adenosine deaminase enzyme, altering its structure and function.
- 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 in the UK by NHS England's Genomic Medicine Service and is listed on several PanelApp panels. These include COVID-19 research, DDG2P, Infantile enterocolitis & monogenic inflammatory bowel disease, Likely inborn error of metabolism (R98), Primary immunodeficiency or monogenic inflammatory bowel disease (R15), Severe combined immunodeficiency with adenosine deaminase deficiency (R16), and Undiagnosed metabolic disorders, indicating its significance in diagnosing various conditions within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the ADA gene?
The ADA gene provides instructions for making the adenosine deaminase enzyme, which is crucial for breaking down deoxyadenosine, a potentially toxic molecule that accumulates during DNA breakdown. This process is especially important for the proper function and development of immune system cells.
How does a faulty ADA gene affect health?
When the ADA gene is faulty, it can lead to a deficiency of the adenosine deaminase enzyme. This results in the accumulation of toxic deoxyadenosine, primarily affecting immune cells and causing a severe inherited immune disorder known as SCID (ADA deficiency).
Is ADA deficiency inherited?
Yes, ADA deficiency is an inherited condition. It follows an autosomal recessive inheritance pattern, meaning an individual must inherit two copies of the altered ADA gene (one from each parent) to develop the condition.
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