Alt. symbols: ADA1

Approved name: adenosine deaminase
Alt. names: adenosine deaminase | adenosine aminohydrolase

Location: 20q13.12: 44584896 - 44652252 (-)
Gene type: protein_coding, 61 transcripts.

Scores: LoFtool: 0.172000 | pLI: 0.00000000 | LOEUF: 1.321

HGNC: 186

NCBI: 100, RefSeq: NG_007385.1

Ensembl: ENSG00000196839.14

LRG_16 | Status: public

OMIM: 608958

Expression | ProteinAtlas

ADA encodes adenosine deaminase 1, a ubiquitous metabolic enzyme with highest levels of expression in lymphoid tissues, brain and gastrointestinal tract. It plays an important role in purine metabolism and extracellular adenosine signaling by catalyzing the irreversible deamination of adenosine and 2-deoxyadenosine (PMID: 8452534, 16670267). Adenosine is an important extracellular signaling molecule whose dysregulation is thought to interfere with normal immune responses. 2-deoxyadenosine irreversibly inhibits the enzyme S-adenosylhomocysteine (SAH) hydrolase, causing SAH accumulation and consequent inhibition of S-adenosylmethionine-mediated methylation processes required for normal thymocyte differentiation (PMID: 7608534). Moreover, increased intracellular uptake of 2-deoxyadenosine followed by phosphorylation by deoxycytidine kinase leads to accumulation of deoxyadenosine triphosphate (dATP), which inhibits ribonucleotide reductase to prevent normal DNA synthesis and repair (PMID: 15705418). ADA has been shown to bind extracellularly to adenosine receptors and act as an allosteric modulator to enhance their ligand affinity via conformational change (PMID: 23193172). It can promote and modulate CD4+ T-cell differentiation and proliferation by binding CD26/DPP4 on CD4+ T cells and ADORA2B receptors on dendritic cells to trigger a co-stimulatory signal for T-cell co-activation (PMID: 20959412). It has also been shown to play a role in lymphocyte-epithelial cell adhesion via CD26/DPP4 binding (PMID: 11772392). ADA isoforms have also been reported with roles in stimulation of plasminogen activation (PMID: 15016824) and male fertility (PMID: 21919946, 26166670).

Biallelic ADA mutations lead to an autosomal recessive (AR) multi-system syndrome [OMIM: 102700] stemming from accumulation of toxic purine metabolites such as adenosine, 2-deoxyadenosine and dATP. Lymphocytes are notably affected, resulting in a spectrum of severities from T-B-NK- severe combined immunodeficiency (SCID) to milder or delayed onset combined immunodeficiency (CID) in ~15–20%. Other manifestations include pulmonary manifestations associated with pulmonary-alveolar proteinosis, skel etal abnormalities, neurodevelopmental impairment, sensorineural hearing loss, and liver disease. The typical presentation is an infant with early onset failure to thrive, persistent diarrhea, dermatitis, and serious infections, often caused by opportunistic pathogens. Physical findings may include absent thymus gland on thoracic X-rays and absence of lymphoid tissues while labs will show lymphocytopenia and hypogammaglobulinemia. Biochemical testing usually shows absent to greatly reduced ADA activity (< 1% of normal), reduced activity of SAH hydrolase in erythrocytes (< 5% of normal), and marked elevation of the metabolite dATP or total dAdo nucleotides (the sum of dAMP, dADP and dATP) in erythrocytes (GeneReviews). However, the common presentation may also be an asymptomatic, healthy-appearing infant in places that perform newborn screening for SCID. Current treatment options include enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplant (HSCT), and autologous gene therapy (GT) (PMID: 29690908). Individuals with ‘delayed onset’ CID generally present with recurrent but less severe infections, particularly sinorespiratory, as well as autoimmunity and atopies with elevated IgE levels (PMID: 22969765). Because of this spectrum of clinical phenotypes, it is important to consider the diagnosis of ADA deficiency even in older individuals, as delay in recognition leads to deterioration in immunological function and the development of irreversible complications. Screening has also identified asymptomatic individuals with ‘partial ADA-deficiency’ who have very low or absent ADA activity in erythrocytes, but greater ADA activity (2–50% of normal) in nucleated cells, resulting in seemingly normal immune function and life expectancy (PMID: 29690908). ADA deficiency is one of the more common causes of AR SCID, accounting for approximately 10–15% of cases in outbred populations and European incidence estimated at ~1:375,000-660,000 live births. Over 70 causative mutations have been identified in patients with either clinical immunodeficiency or unaffected individuals with partial enzyme deficiency - approximately 60% are missense, 20% are splicing, 9% are small deletions, 7% are nonsense, and 3% are intragenic deletions involving one or multiple exons (GeneReviews). The level of metabolic substrates and genotype correlate with the severity of the clinical phenotype (PMID: 9758612). [Load More]