Alternative titles; symbols
HGNC Approved Gene Symbol: ADA
Cytogenetic location: 20q13.12 Genomic coordinates (GRCh38): 20:44,619,522-44,651,699 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.12 | Adenosine deaminase deficiency, partial | 102700 | Autosomal recessive; Somatic mosaicism | 3 |
| Severe combined immunodeficiency due to ADA deficiency | 102700 | Autosomal recessive; Somatic mosaicism | 3 |
The ADA gene encodes adenosine deaminase (EC 3.5.4.4), an enzyme that catalyzes the irreversible deamination of adenosine and deoxyadenosine in the purine catabolic pathway. See DPP4 (102720) for description of an adenosine deaminase complexing protein.
Wiginton et al. (1983) isolated partial ADA cDNA sequences from a human T-cell lymphoblast cDNA library. Northern blot analysis detected a minor 5.8-kb and a major 1.6-kb mRNA transcript. ADA immunoreactive protein and translatable ADA mRNA were found to be 6 to 8 times higher in T-lymphoblast lines than in B-lymphoblast lines, which corresponded to increased ADA catalytic activity and protein in T cells compared to B cells. The differences are due mainly to differences in the rate of degradation of the ADA protein.
Valerio et al. (1984) isolated a full-length ADA cDNA encoding a 363-amino acid protein with a molecular mass of 40 kD.
Valerio et al. (1985) determined that the ADA gene spans 32 kb and contains 12 exons. Wiginton et al. (1986) reported the complete sequence and structure of the human ADA gene. Kalman et al. (2004) stated that the ADA gene contains 10 exons.
By somatic cell hybridization, Creagan et al. (1973) and Tischfield et al. (1974) mapped the ADA gene to chromosome 20. Valerio et al. (1984) used an ADA cDNA probe in Southern hybridizations with DNA from a hybrid cell panel to assign the gene to chromosome 20. Mohandas et al. (1984) reported that the genes for ADA and SAHH are on separate parts of 20q, separated by 20q13.1.
Gene dosage studies of adenosine deaminase and inosine triphosphatase provided corroboration of partial trisomy 20 diagnosed cytogenetically (Rudd et al., 1979). Nielsen et al. (1986) studied ADA in a case of partial trisomy 20q resulting from a familial t(3;20) translocation. Gene dosage studies seemed to exclude the ADA gene from the distal part of 20q (20q13.1-qter). By dosage effect in a patient with deletion of 20q, Petersen et al. (1987) assigned the ADA locus to 20q13.11.
By means of in situ hybridization to high resolution spreads of somatic and pachytene chromosomes, Jhanwar et al. (1989) localized the ADA gene to 20q12-q13.11.
Rothschild et al. (1993) identified and mapped new dinucleotide repeat polymorphisms associated with the ADA locus.
Severe Combined Immunodeficiency due to ADA Deficiency
In cell lines from 2 patients with severe combined immunodeficiency (SCID) due to ADA deficiency (102700), Adrian and Hutton (1983) and Wiginton et al. (1983) found 3- to 4-fold increased levels of normal translatable ADA mRNA compared to normal controls. The authors suggested that the cellular ADA deficiency was secondary to rapid degradation of a defective ADA protein. Similar results were found by Adrian et al. (1984).
In patients with SCID due to ADA deficiency, Akeson et al. (1987) identified several biallelic mutations in the ADA gene (see, e.g., 608958.0004; 608958.0006; 608958.0017).
Tzall et al. (1989) identified and/or characterized at least 9 RFLPs at the ADA locus and studied these in 17 patients with complete ADA deficiency and in 10 patients with partial ADA deficiency. Genetic compounds and homozygous haplotypes were identified among both types of patients.
Delayed or Late Onset
In 7 patients with delayed or late onset of SCID due to ADA deficiency, Santisteban et al. (1993) identified mutations in the ADA gene (see, e.g., 608958.0020 and 608958.0032).
Partial ADA Deficiency
In 7 patients with partial ADA deficiency identified by a New York State newborn screening program, Hirschhorn et al. (1990) identified biallelic mutations in the ADA gene (608958.0010-608958.0015). Six of the 7 children either came from a limited area in the Caribbean or shared a black ethnic background, suggesting a founder effect; however, the finding of multiple new mutations suggested that partial ADA deficiency offered a selective advantage.
Gene Reversion
Hirschhorn et al. (1994, 1996) described unusual cases of somatic mosaicism due to in vivo reversion to normal of an inherited mutation in the ADA gene (608958.0024; 608958.0032).
By means of a new and specific method, Spencer et al. (1968) demonstrated isozymes of erythrocyte adenosine deaminase and showed that there are 3 genetically determined phenotypes: ADA-1, ADA-2/1 and ADA-2. The frequency of the ADA-2 allele was estimated at 0.06 in Europeans, 0.04 in Blacks, and 0.11 in Asiatic Indians. Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
In mice overexpressing Il13 (147683) in the lung, Blackburn et al. (2003) observed pulmonary inflammation and remodeling accompanied by a progressive increase in adenosine accumulation, inhibition of ADA activity and mRNA accumulation, and increased expression of several adenosine receptors (see 102776). Ada enzyme therapy diminished the Il13-induced increase in adenosine, inhibited Il13-induced inflammation, chemokine elaboration, fibrosis, and alveolar destruction, and prolonged the survival of Il13 transgenic mice. Il13 was strongly induced by adenosine in Ada-null mice. Blackburn et al. (2003) concluded that adenosine and adenosine signaling contribute to and influence the severity of IL13-induced tissue responses and that IL13 and adenosine stimulate one another in an amplification pathway.
This variant, formerly titled SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-NEGATIVE, DUE TO ADENOSINE DEAMINASE DEFICIENCY, has been reclassified based on the findings of Bell et al. (2011).
In a patient with SCID due to ADA deficiency (102700) originally reported by Hirschhorn et al. (1975), Valerio et al. (1986) identified compound heterozygosity for 2 mutations in the ADA gene: lys80 to arg (K80R) and L304R (608958.0005).
In a preconception carrier screen for 448 severe recessive childhood diseases involving 437 target genes, Bell et al. (2011) found that the K80R mutation in ADA is a polymorphism carried by unaffected individuals.
In a patient with SCID due to ADA deficiency (102700), Akeson et al. (1988) identified compound heterozygosity for 2 mutations in the ADA gene: a C-to-T transition, resulting in an arg101-to-trp (R101W) substitution, and R211H (608958.0004). Functional expression studies showed that the mutant genes were transcribed into normal mRNA but did not encode functional proteins.
In T cells from the patient reported by Akeson et al. (1988) with the R101W and R211H mutations, Arredondo-Vega et al. (1990) found that the R101W mutation could be expressed selectively in IL2-dependent T cells as a stable, active enzyme. Cultured T cells from other patients with the R211H mutation did not express significant ADA activity, whereas some B-cell lines from a patient with an R101Q (608598.0003) mutation had normal ADA activity. Arredondo-Vega et al. (1990) speculated that arg101 may be at a site that determines degradation of ADA by a protease that is under negative control by IL2 in T cells, and is variably expressed in B cells.
In a cell line from a patient with SCID due to ADA deficiency (102700), Bonthron et al. (1985) identified a G-to-A transition in exon 4 of the ADA gene, resulting in an arg101-to-gln (R101Q) substitution. Since the predicted primary structure of the enzyme was normal, the mutation was apparently responsible for loss of function in the gene.
In a patient with SCID due to ADA deficiency (102700), Akeson et al. (1987) identified compound heterozygosity for 2 mutations in the ADA gene: a G-to-A transition in exon 7, resulting in an arg211-to-his (R211H) substitution, and A329V (608958.0006). In another SCID patient, Akeson et al. (1988) identified compound heterozygosity for the R211H and R101W (608958.0002) mutations. Functional expression studies showed that the mutant genes were transcribed into normal mRNA, but did not encode functional proteins.
In a 5-year-old Japanese male patient with SCID due to ADA deficiency, Onodera et al. (1998) identified the R211H substitution caused by a 632G-A transition in the ADA gene. The patient had been receiving periodic infusions of genetically modified autologous T lymphocytes carrying the transduced ADA gene. ADA enzyme activity in the patient's circulating T cells, which was only marginally detected before gene transfer, increased to levels comparable to those of a heterozygote carrier and was associated with increased T-lymphocyte counts and improvement of the patient's immune function.
In a patient with SCID due to ADA deficiency (102700) originally reported by Hirschhorn et al. (1975), Valerio et al. (1986) identified compound heterozygosity for 2 mutations in the ADA gene: a T-to-G transversion in exon 10, resulting in a leu304-to-arg (L304R) substitution and K80R (608958.0001). Functional expression studies showed that the L304R substitution resulted in ADA enzyme inactivation.
In a patient with SCID due to ADA deficiency (102700), Akeson et al. (1987) identified compound heterozygosity for 2 mutations in the ADA gene: a 1081C-T transition in exon 11, resulting in an ala329-to-val (A329V) substitution, and R211H (608958.0004). A second patient was compound heterozygous for A329V and a deletion of exon 4 (608958.0017). Functional expression studies showed that the mutant genes were transcribed into normal mRNA but did not encode functional proteins.
In a SCID patient, Markert et al. (1989) identified the A329V mutation in exon 11 of the ADA gene. The authors found that 5 of 13 patients (7 of 22 alleles) had the same A329V mutation and that A329V was associated with 3 distinct ADA haplotypes. The findings did not support a founder effect.
Hirschhorn et al. (1992) found that 5 missense mutations accounted for one-third of 45 ADA-negative chromosomes studied. The A329V mutation was the most frequent, being found in 4 persons heterozygous for the mutation and 1 person homozygous for the mutation (6/45 alleles).
In a Belgian female infant with SCID and ADA deficiency (102700), born of consanguineous parents, Berkvens et al. (1987) identified a homozygous 3.2-kb deletion spanning the promoter and the first exon of the ADA gene. No ADA-specific mRNA was detected in the patient's fibroblasts, indicating a null allele. Both parents and an unaffected brother were heterozygous for the mutation.
Markert et al. (1988) identified a 3.3-kb deletion in the ADA gene in an American patient with ADA deficiency and SCID who had no lymphocyte ADA enzyme activity, no detectable ADA mRNA, and a deletion in the region of the first exon of the ADA gene. Markert et al. (1988) determined that the deletion of the ADA promoter and first exon resulted from homologous recombination between 2 repetitive DNA sequences of the Alu family. By direct sequencing, Berkvens et al. (1990) showed that the 3.25-kb deletion was due to recombination within the left arms of 2 direct AluI repeats. They noted that the mutation was identical to that in the unrelated patient reported by Markert et al. (1988); however, neither the pedigree of the Belgian family nor a comparison of haplotype data suggested a relationship between the American and Belgian patients.
In a patient with SCID due to ADA deficiency, Jiang et al. (1997) identified compound heterozygosity for the exon 1 deletion and 2 mutations on the same allele (608958.0029). Three of 4 additional unrelated patients tested had the exon 1 deletion, suggesting that it is relatively common. The authors noted that the exon 1 deletion accounted for 10% of almost 100 chromosomes studied by several laboratories, but was easily missed by generally used methods of mutation detection.
In 2 unrelated patients with partial ADA deficiency (102700) who were immunocompetent, Hirschhorn et al. (1989) identified a C-to-A transversion in exon 10 of the ADA gene, resulting in a pro297-to-gln (P297Q) substitution. One patient was homozygous for the mutation and the other was compound heterozygous. The P297Q mutation resulted in a heat-labile enzyme.
In 3 patients with partial ADA deficiency who lacked ADA activity in erythrocytes but retained ADA activity in lymphocytes (102700), Hirschhorn et al. (1990) identified a 226C-T transition in exon 4 of the ADA gene, resulting in an arg76-to-trp (R76W) substitution. The R76W mutant allele resulted in an abnormally acidic protein with 16% normal activity in lymphoid cells. One patient was homozygous and the other 2 were compound heterozygous (see also 608958.0012 and 608958.0013). All 3 patients were from the West Indies, and the authors postulated a selective advantage of carrying a mutant allele for partial ADA deficiency.
In a patient with partial ADA deficiency (102700), Hirschhorn et al. (1990) identified a 446G-A transition in the ADA gene, resulting in an arg149-to-gln (R149Q) substitution. The R149Q mutant allele resulted in a mildly acidic protein with 42% residual activity.
In a patient with partial ADA deficiency (102700), Hirschhorn et al. (1990) identified compound heterozygosity for 2 mutations in the ADA gene: an 821C-T transition in exon 9, resulting in a pro274-to-leu (P274L) substitution, and R76Y (608958.0010). The P274L mutant allele resulted in an abnormally basic protein with 12% normal activity in lymphoid cells.
In 2 unrelated patients with SCID due to ADA deficiency (102700), Hirschhorn et al. (1990) identified a 320T-C transition in exon 4 of the ADA gene, resulting in a leu107-to-pro (L107P) substitution. Analysis of enzyme activity showed that the L107P mutation is a null allele.
In a patient with partial ADA deficiency (see 102700), Hirschhorn et al. (1990) identified compound heterozygosity for 2 mutations in the ADA gene: a 631C-T transition, resulting in an arg211-to-cys (R211C) substitution, and L107P (608958.0013). The R211C mutant allele resulted in an abnormally acidic protein with 8% normal activity in lymphoid cells.
In 2 sisters with adult-onset ADA deficiency, Shovlin et al. (1994) identified compound heterozygosity for 2 mutations in the ADA gene. The paternal allele contained a deletion resulting from homologous recombination between 2 Alu elements, predicting a null phenotype. The maternal allele had a C-to-T transition in a CpG dinucleotide that changed the codon for arginine-211, which lies in a conserved sequence close to the active site, to cysteine. This mutation had previously been observed in a child thought to have partial ADA deficiency by Hirschhorn et al. (1990) (608958.0013). Shovlin et al. (1994) suggested that immune function in children with partial ADA deficiency may deteriorate with time.
In a patient with partial ADA deficiency (see 102700), Hirschhorn et al. (1990) identified a homozygous 643G-A transition in exon 7 of the ADA gene, resulting in an ala215-to-thr (A215T) substitution. The A215T mutant allele resulted in an abnormally basic protein with 8% residual activity in lymphoid cells.
In a patient with SCID due to ADA deficiency (102700), Hirschhorn et al. (1991) identified a homozygous 646G-A transition in exon 7 of the ADA gene, resulting in a gly216-to-arg (G216R) substitution. The patient was the offspring of consanguineous Amish parents from eastern Pennsylvania. Computer analysis of secondary structure predicted a major alteration with loss of a beta-pleated sheet in a highly conserved region of the protein. Onset of symptoms was at 3 days of age with respiratory distress from pneumonia unresponsive to antibiotics. Of 9 patients, this one had the highest concentration of the toxic metabolite deoxy-ATP and a relatively poor immunologic response during the initial 2 years of therapy with polyethylene glycol-adenosine deaminase. Heterozygosity for the same mutation was found in 2 of 21 additional patients with ADA-SCID.
In a patient with SCID due to ADA deficiency (102700), Akeson et al. (1987) identified compound heterozygosity for 2 mutations in the ADA gene: a deletion of exon 4 and A329V (608958.0006). Akeson et al. (1988) found that the exon 4 deletion was caused by an A-to-G transition in the 3-prime splice site of intron 3. Functional expression studies showed that the mutant gene was transcribed into normal mRNA but did not encode a functional protein.
In a patient with SCID due to ADA deficiency (102700) who was unusual for responding to the limited form of enzyme therapy provided by repeated partial exchange transfusions (Polmar et al., 1976; Dyminski et al., 1979), Hirschhorn (1992) identified compound heterozygosity for 2 mutations in the ADA gene: a 466C-T transition, resulting in an arg156-to-cys (R156C) substitution and L304R (608958.0005).
In a patient with SCID due to ADA deficiency (102700) who was unusual for responding to the limited form of enzyme therapy provided by repeated partial exchange transfusions (Polmar et al., 1976; Dyminski et al., 1979), Hirschhorn (1992) identified compound heterozygosity for 2 mutations in the ADA gene: an 872C-T transition in exon 10, resulting in a ser291-to-leu (S291L) substitution and A329V (608958.0006).
In a patient with late-onset SCID due to ADA deficiency (102700), in whom the diagnosis of ADA deficiency was first made at the age of 15 years, Santisteban et al. (1993) identified a homozygous -34G-A transition in intron 10 of the ADA gene, converting a GG dinucleotide to AG, resulting in a new splice acceptor site with all the cis-acting elements of a functional 3-prime splice junction. Besides introducing 9 new codons after leu325, use of the cryptic splice site shifted the reading frame to include 268 bp of the normal 3-prime noncoding region before a new TGA stop codon was generated 16 bp from the poly(A) addition signal. The mutant protein was predicted to consist of 463 residues, compared to the normal 363 residues.
Hirschhorn et al. (1994) determined that the common electrophoretic variant of ADA, the ADA2 allozyme (ADA*2), is caused by a 22G-A transition in the ADA gene, resulting in an asp8-to-asn (D8N) substitution. The ADA2 allozyme is a more basic electrophoretic variant that is codominantly inherited with the usual ADA1 allozyme. Functional expression studies of the D8N protein confirmed expression of an enzyme that comigrated with a naturally occurring ADA2 allozyme. Hirschhorn et al. (1994) noted that the ADA2 allozyme has been found in all populations studied and results in only minimally reduced enzyme activity in erythrocytes. The gene frequency of the ADA2 allozyme is estimated as 0.06 in Western populations, lower among individuals of African descent, and higher in Southeast Asian populations. The ADA2 allele was also found on at least 2 different genetic backgrounds, 1 of Ashkenazi Jewish ancestry and 1 in a large Mormon pedigree from Utah, suggesting independent recurrence of the mutation. Consistent with independent recurrence, the G-to-A transition was located in a CpG dinucleotide of the type subject to a high frequency of mutation. Hirschhorn et al. (1994) also found a probable intragenic crossover in the very large first intron that is rich in repetitive DNA sequences.
In 2 Italian groups of autistic children, Bottini et al. (2001) found a significantly higher frequency of the low-activity ADA2 allele than in controls. They suggested that this genotype-dependent reduction in ADA activity may be a risk factor for the development of autism.
In 2 sisters with SCID due to ADA deficiency (102700) reported by Umetsu et al. (1994), Arredondo-Vega et al. (1994) identified compound heterozygosity for 2 splice site mutations in the ADA gene: a G-to-A transition at the +1 position of the 5-prime splice site of IVS2, and a complex 17-bp rearrangement of the 3-prime splice site of IVS8, resulting in a 7-purine insertion into the polypyrimidine tract and alteration of the reading frame of exon 9 (608958.0023). The sisters showed a disparity in clinical phenotype, with residual ADA activity in cultured T cells, fibroblasts, and B lymphoblasts of one, but no detectable activity in the cells of the other. ADA mRNA was undetectable by Northern blot analysis in the cells of both patients. PCR-amplified ADA cDNA mutant clones showed premature translation stop codons, consistent with these mutations. However, some cDNA clones from T cells of both patients and from fibroblasts and EBV-transformed B cells of the first patient were normally spliced at both the exon 2/3 and 8/9 junctions. A normal coding sequence was documented for clones from both sibs. Arredondo-Vega et al. (1994) suggested that a low level of normal pre-mRNA splicing may occur despite mutation of the invariant first nucleotide of the 5-prime splice donor sequence, and that differences in efficiency of such splicing may account for the difference in residual ADA activity, immune dysfunction, and clinical severity in the 2 sibs.
For discussion of the complex 17-bp rearrangement of the 3-prime splice site of IVS8 in the ADA gene, resulting in a 7-purine insertion into the polypyrimidine tract and alteration of the reading frame of exon 9, that was identified in compound heterozygous state in sibs with SCID due to adenosine deaminase deficiency (102700) by Arredondo-Vega et al. (1994), see 608958.0022.
In a 2.5-year-old patient with SCID due to ADA deficiency (102700), Hirschhorn et al. (1994) identified compound heterozygosity for 2 mutations in the ADA gene: a +1G-C transversion at the donor splice site in IVS1, and R101Q (608958.0003). The patient's disease course improved, and he was healthy by age 16 years. Cell lines established at age 16 showed 50% of normal ADA activity; 50% of ADA mRNA had normal sequence, and 50% had the R101Q mutation. Genomic DNA contained the missense mutation but not the splice site mutation. The authors postulated somatic mutation or reversion at the site of the mutation.
In a newborn with hepatic dysfunction as a complication of SCID due to ADA deficiency (102700), Bollinger et al. (1996) identified compound heterozygosity for 2 mutations in the ADA gene: a G-to-T transversion, resulting in a gly74-to-val (G74V) substitution, and A329V (608958.0006).
In a patient with a mild form of SCID due to ADA deficiency (102700), Hirschhorn et al. (1996) identified compound heterozygosity for 2 mutations in the ADA gene: a G-to-A transition in intron 5, resulting in deletion of exon 5, and R156H (608958.0032). The splice site mutation was inherited from the father and the R156H mutation was inherited from the mother.
In an Afghan boy with partial ADA deficiency (see 102700) identified through newborn screening in New York State, Hirschhorn et al. (1997) identified a homozygous 454C-A transversion of the ADA gene resulting in a leu152-to-met (L152M) substitution. The child was born of consanguineous parents. Functional expression studies showed that the L152M mutation had considerably less enzymatic activity than the pathogenic R211C (608958.0014) mutation. The child had the highest level of the accumulated metabolite dATP among the 13 partially ADA-deficient patients studied, but considerably less dATP than those with immunodeficiency. The authors concluded that the L152M mutation could result in disease in homozygous individuals challenged by severe environmental insult, or in heterozygous individuals when combined with a null mutation.
In a healthy adult male of Afghan Kung descent with partial ADA deficiency (see 102700), Hirschhorn et al. (1997) identified a homozygous 698C-T transition in the ADA gene, resulting in a thr233-to-ile (T233I) substitution. Functional expression studies showed that the T233I mutation had 16 to 20% normal enzyme activity, which was slightly greater than the pathogenic R211C (608958.0014) mutation. Immunologic studies done previously on the patient indicated an unstable ADA enzyme that was absent in red blood cells but present in sufficient amounts in other cell types to prevent accumulation of toxic metabolites and resulting immunodeficiency.
In a patient with SCID due to ADA deficiency (102700), Jiang et al. (1997) identified compound heterozygosity for 2 mutant ADA alleles. One allele, inherited from the mother, contained 2 mutations in exon 4: a 290A-G transition, resulting in a tyr97-to-cys (Y97C) substitution, and a 316C-G transversion, resulting in a leu106-to-val (L106V) substitution. The second allele, inherited from the father, was a deletion (608958.0008). The patient was diagnosed prenatally in a family with an affected child previously reported by Moen et al. (1987), and the diagnosis was confirmed after birth by demonstration of less than 1% ADA activity in red blood cells and mononuclear cells. Functional expression studies showed that the L106V mutation resulted in 30% of normal activity, similar to that of partial mutations, and the Y97C mutation resulted in 1.5% of normal activity. The presence of both mutations on the same allele virtually abolished detectable enzyme activity to less than 0.01%. Crystallographic structure analysis showed that the L106V mutation surrounds the opening of the active site and is predicted to reduce the stability of substrate binding. The Y97C mutation resides within the active site and interacts with salt ridges that play a role in the catalytic mechanism of ADA.
In 4 patients from 3 Saudi Arabian families with delayed onset of immune deficiency (102700), Arredondo-Vega et al. (2002) identified homozygosity for a 31701T-A transversion in the last splice acceptor site of the ADA gene. By converting TG to AG, this mutation activated a cryptic splice site, inserting the last 13 nucleotides of intron 11 into ADA mRNA, which resulted in addition of a 43-residue C-terminal tail that rendered the protein unstable. When mutant cDNA from 3 patients was expressed in E. coli, only 1% of the ADA activity obtained with wildtype cDNA was yielded. The oldest patient, 16 years old at diagnosis, had greater residual immune function and less elevated erythrocyte deoxyadenosine nucleotides than his 4-year-old affected sister. In addition to being homozygous for the intron 11 mutation, he also carried a deletion of 11 adjacent downstream nucleotides (608958.0031).
In a patient with late-onset of SCID due to ADA deficiency (102700) who was diagnosed at age 16 years, Arredondo-Vega et al. (2002) identified the homozygous intron 11 mutation (608958.0030) and an 11-bp deletion of adjacent basepairs 31702-31712, which suppressed aberrant splicing and excised an unusual purine-rich tract from the wildtype intron 11/exon 12 junction. Despite serious sequelae of early infections, this patient had apparently stabilized at some time during childhood. His T cells and Epstein-Barr virus (EBV) B-cell line had 75% of normal ADA activity and ADA protein of normal size. The authors noted that the mild atypical features of this patient were caused by an unusual form of somatic reversion: second-site suppression of a cryptic splice site. However, after several months of PEG-ADA treatment, the patient had lower ADA activity than before treatment, and the authors suggested that therapy allowed the ADA-deficient lymphoid cells to survive and proliferate.
In 3 patients with delayed or late onset of SCID due to ADA deficiency (102700), Santisteban et al. (1993) identified a heterozygous 467G-A transition in exon 5 of the ADA gene at a CpG hotspot, resulting in an arg156-to-his (R156H) substitution. All 3 patients were compound heterozygous for R156H and a mutation predicted to result in an inactive enzyme; 1 patient also carried the G216R (608958.0016) mutation. Functional expression studies showed that the R156H mutant enzyme retained 1.5 to 2% residual activity.
In a patient with a mild form of SCID due to ADA deficiency, Hirschhorn et al. (1996) identified compound heterozygosity for the R156H mutation, inherited from the mother, and a splice site mutation (608958.0026) inherited from the father. The patient showed clinical improvement without therapy, and analysis at the age of 11 years revealed that the R156H mutation had undergone in vivo reversion to normal in lymphoid cell lines and in a subset of peripheral blood cells. The authors concluded that the somatic mosaicism caused the relatively mild phenotype.
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