Alt. symbols: IDGFL | CECR1 | ADGF

Approved name: adenosine deaminase 2
Alt. names: cat eye syndrome chromosome region, candidate 1

Location: 22q11.1: 17178790 - 17258235 (-)
Gene type: protein_coding, 30 transcripts.

Scores: LoFtool: 0.161000 | pLI: 0.00005253 | LOEUF: 1.070

HGNC: 1839

NCBI: 51816, RefSeq: NG_033943.1

Ensembl: ENSG00000093072.19

LRG_1217 | Status: public

OMIM: 607575

Expression | ProteinAtlas

ADA2 encodes a secreted enzyme predominantly expressed by myeloid and endothelial cells that regulates purine metabolism by breaking down extracellular signaling molecules adenosine and 2′-deoxyadenosine at sites of inflammation. ADA2 requires elevated adenosine levels for optimal enzyme activity, approx to 100 uM, which is several fold higher than the normal extracellular Adenosine concentration. For this reason the deamination of extracellular Adenosine by ADA2 is still debated. Independently of its enzymatic activity, ADA2 is also thought to exert growth factor-like properties by binding cell surfaces via proteoglycans to help regulate cell proliferation and differentiation (PMID: 20453107, 20147294). It has more recently been suggested that ADA2 is a lysosomal DNase that contributes to type I IFN activation via this role, but this is not currently a widely accepted stance (doi.org/10.1101/2020.06.21.162990).

Biallelic ADA2 mutations lead to deficiency of adenosine deaminase 2 (DADA2) [OMIM: 615688], a pleiotropic and multi-faceted AR syndrome characterized by early-onset recurrent fevers and variable degrees of vasculopathy/vasculitis ranging from livedo racemosa and reticularis to polyarteritis nodosa to recurrent life-threatening ischemic and/or hemorrhagic strokes. Hematologic complications may present as pure red cell aplasia, immune cytopenias or bone marrow failure, while immunodeficiency can present as a CVID-like phenotype with or without lymphoproliferative features (PMID: 29951947, 34845942). Patients with DADA2 have been identified globally, with prevalence estimated at as high as 1:25,000, based on allele frequencies of in silico-predicted ADA2 damaging variants. However, carrier frequencies for the two most common mutations (Gly47Arg and Arg169Gln) in specific populations may be much higher (1:10-500) as a consequence of founder population and population bottleneck effects (PMID: 29391253, GeneReviews). ADA2 mutations are located throughout the protein and can affect a broad spectrum of functions, including catalytic activity, dimerization and interactions with other proteins, and enzyme trafficking and secretion via N-glycosylation (PMID: 30406060). Carrier heterozygotes are unaffected as far as known. Historically, few to no genotype-phenotype correlations were identified, but more recent data suggests that disease severity may correlate with enzyme activity, with low or absent activity associated with severe hematological manifestations, and higher residual activity linked to inflammatory vascular phenotypes (PMID: 31945408). Please see entry on Sneddon syndrome for specific discussion of this phenotypic label. [Load More]