Gene: [20q1311/ADA] adenosine deaminase (adenosine aminohydrolase); immune deficiency, severe combined (due to ADA deficiency);


According to Jhanwar-1989 (experiments on in situ hybridization on chromosomes with a gene-specific DNA probe), ADA was located in region q12-13.11 and the localization to subsegment q13.2 or more distally, suggested earlier and given in HGM10, has been disproved conclusively. The HUGEN in this case accepts the data of Petersen-1987."


ADA, a key enzyme in purine metabolism, catalyzes the irreversible deamination of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively. This ubiquitous enzyme is often classified as a "housekeeping" protein. In some tissues ADA is developmentally regulated."


Human adenosine deaminase exists as either a large and/or small molecular form in various tissues. The small form is a catalytically active protein (MM 36-38 kD) (Van der Weyden-1976). The large form (MM 298 kD) is a complex of the small form and a nonenzymatic binding protein (Daddona-1982). The adenosine deaminase-binding protein may function to regulate the clearance of adenosine deaminase from serum and further may anchor the enzyme to the external surface of the cell membrane where it can function in regulating plasma adenosine concentrations and/or purine nucleoside transport (Schrader-1983; Andy-1982). Adenosine deaminase purified from human erythrocytes is a soluble monomeric protein with an estimated MM 38 kD (Schrader-1976; Daddona-1977)."


[1] Molecular analysis has demonstrated the following types of mutations that cause ADA deficiency (ADA-SCID):
(1) point mutations that alter the protein structure and/or stability;
(2) point mutations or deletions that alter transcription or splicing of ADA mRNA;
(3) still undefined mutations, which cause partial ADA deficiency and appear to affect protein stability.
[2] Bonthron-1985 and Valerio-1986 have demonstrated that in certain cases the ADA-SCID was caused by single base-pair substitutions in the coding region of the ADA gene itself. Later a homozygous 3.2-kb deletion spanning the promoter and first exon in the ADA gene was found to have caused ADA-SCID disease in a female infant born to a consanguineous Flemish couple (Berkvens-1987).
[3] The mutation(s) leading to increased ADA activity is still unknown.
[4] Both the clinical and biochemical effects of the mutations are strikingly different among individuals. Some mutations are associated with an unstable ADA protein, total deficiency of ADA activity in erythrocytes, partial deficiency of ADA activity in peripheral lymphocytes, and absence of clinical disease (Hirschhorn-1979). Other mutations have resulted in the virtual absence of ADA activity in erythrocytes and lymphocytes and cause severe combined immunodeficiency disease (Martin-1981; Wiginton-1982; Hirschhorn-1979; Daddona-1980; Adrian-1983). Within the second group, there are a number of distinct mutations, as indicated by the amount of mutant ADA protein detectable by radioimmunoassay in extracts of cell lines carrying those mutations (Wiginton-1982; Daddona-1980)."


[1] Inherited deficiency of the enzyme adenosine deaminase (ADA) accounts for about one-fourth of cases of autosomal recessive form of severe combined immunodeficiency disease (SCID) in children (Giblett-1972; Martin-1981; Mitchell-1980).
[2] ADA-deficient patients (ADA-SCID) lack both T-and B-cell function and have dramatically reduced levels of ADA catalytic activity and immunoprecipitable ADA protein. There appears to be a threshold of ADA activity required for correct function of lymphocytes, since partial ADA-deficient subjects, with 20-50% of normal ADA catalytic activity in lymphoid cells, are immunocompetent.
[3] A marked increase in adenosine deaminase has been associated with acute lymphoblastic leukemia and with a hereditary form of hemolytic anemia (Smyth-1978; Meier-1976; Valentine-1977; Van der Weyden-1976)."


[1] The gene (Petersen-1987) includes 32,040 bp, from the major transcription initiation site to the polyadenylation site. This relatively large gene has 12 exons separated by 11 introns. The exons range in size from 62 to 325 bp. The average size is 125 bp. The introns vary enormously in size, randing from 76 to 15166 bp. In general, the intronic sequence near the junction is more conserved than the exonic sequence is, relative to the consensus sequence.
[2] The exons are unevenly distributed, with exon 1, containing the entire 5'-noncoding region plus codons for the first 11 amino acids, separated from exon 2 by an intron of 15,166 bp. (Intron 1 comprises more than 47% of the total exon-intron sequence.) Exons 2 and 3 are separated by another fairly large intron of 7,052 bp, while exons 3 through 12 are all encoded within 10,000 bp. Exon 12 contains all of the final three amino acid codons as well as the entire 3'-noncoding region. The human gene for another enzyme of the purine salvage pathway, hypoxanthine phosphoribosyl transferase (GEM:0Xq261/HPRT1), has a simular structure. However, in this case both exons 1 and 2 and exons 3 and 4 are separated by large introns of over 13,000 bp (Stout-1985).
[3] The body of the gene (nucleotides 1-32040) is slightly G/C rich (A, 22.1%; C, 26.6%, G, 26.6%; and T, 24.8%, on the mRNA-like strand). Analysis of the dinucleotide frequencies compared to those expected from random distribution shows that only CG (1.7% found, 7.1% predicted) is significantly different from the predicted frequency. Underrepresentation of CG dinucleotide is a well-established characteristic of eucaryotic DNA (Nussinov-1981).
[4] Several types of repetitive sequences are present in the human adenosine deaminase gene and flanking region. The most common type is the ubiquitous Alu family of dispersed repeats (Jelinek-1982). Twenty-three copies of this repeat are present within the sequenced area, accounting for 18% of the total sequence. The Alu repeats are found in both orientations. Four of the Alu repeat sequences are truncated relative to the normal repeat unit of approximately 300 nucleotides, and each of these truncated repeats is located near the tail end of another complete Alu unit. All but one of the Alu repeat areas are flanked by unique short direct repeats of 5-20 nucleotides. Seventeen of the Alu repeats are clustered in the first two introns. Another repetitive sequence represents a copy of the 'O' family (Sun-1984). These repeats of approximately 350 bp have recently been proposed as the long terminal repeats for a transposon-like element (Paulson-1985).
[5] The ADA gene lacks the characteristic eukaryotic promoter elements, the TAATA and CAAT boxes. Instead, within the 5'-flanking region of exon 1, there are six GC-rich decanucleotide sequences that are highly homologous to sequences identified as functional binding sites for the transcription factor Sp1. Sp1 has been shown to bind and activate transcription from several viral and cellular promoters similar to those present in the ADA gene (Kadonaga-1986). Several of the so called "housekeeping" genes, including HPRT (Melton-1984), dihydropholate reductase (GEM:05q1/DHFR) (Chen-1984), and glucose 6-phosphate dehydrogenase (GEM:0Xq28/G6PD) (Martini-1986), have similar GC-rich promoters.
[6] Comparison to cDNA sequences: The exonic sequences of the gene were compared to the previously published ADA211 cDNA sequence (Adrian-1984). Three sequence differences were noted. The G at position 25915 in exon 5 of the gene instead of A (at 390) in ADA211 and the A at position 27296 in exon 6 of the gene instead of G (at 534) in ADA211 represent wobble in the third base of a Val codon. These first two differences probably represent allelic variation since both of the alternative nucleotides at these locations have been observed previously in normal human adenosine deaminase cDNAs (Wiginton-1984; Daddona-1984; Valerio-1984; Bonthron-1985). The third difference is a C at position 84 in the first exon of the gene which is missing in the published ADA211 sequence. When this cDNA was sequenced again, this difference was revealed as an artifactual error in the original sequencing gels, and a C should be present at this location in the ADA211 cDNA sequence as well. Sequence differences among adenosine deaminase cDNAs have been tabulated previously (Bonthron-1985). The availability of the entire gene sequence should be beneficial in determining the basis of mutations resulting in adenosine deaminase deficiency, not only those involving point mutations and amino acid substitutions, as has been done in two cases (Bonthron-1985; Valerio-1986), but also those involving larger segments of DNA (Adrian-1984), possibly including intronic sequences."


Hereditary adenosine deaminase deficiency with severe combined immunodeficiency has been proposed as one of the most promising candidates for initial attempts at human gene therapy (Anderson-1984). Knowledge of the sequence, structure, and regulation of the normal human adenosine deaminase gene may be critical to the success of such an endeavor."


[1] A soluble protein is widely distributed in the cytoplasm of all cells, but it is highest in lymphoid cells, such as those of the thymus, spleen, and lymph nodes (Van der Weyden-1976; Hirschhorn-1978; Adams-1976).
[2] Levels are notably high in immature T lymphocytes (Adams-1976; Tung-1976; Barton-1979; Smith-1976).
[3] In red blood cells, ADA is synthesized as a 33-kD peptide. In other tissues, this monomer forms a functional enzyme representing a homomultiner (MM up to 200 kD), in complex with the conversion factor (complex-forming protein ADCP."


Two ADCP isoforms are supposed to be encoded by different structural genes (GEM:06^/ADACF1 and GEM:02q243/DPP4)."


[1] Probe pLL is a virtually full-sized 1.41-kb cDNA cloned in the plasmid pBR322 (Valerio-1984).
[2] Probe lambda-ADA211 is a 1.462 kb cDNA fragment cloned at HindIII site in the plasmid pBR322 (Hutton JJ)."


ApaI-(A)RFLP (PRO[2]): A1= 6.6 kb (f=0.20); A2= 3.7/2.9 (0.80); (Gribbin-1989)"


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nucm, imm, onc


coding, basic


20 q13.11


MIM: 102700