Adenosine Deaminase Deficiency In Humans Research Articles

Whole exome sequencing reveals a missense mutation in the ADA gene causing severe combined immune deficiency in a Pakistani family ADA gene mutation causing SCID

BACKGROUND & OBJECTIVE: Human adenosine deaminase deficiency, OMIM 102700 (ADA deficiency) is a genetic disorder which causes severe combined immunodeficiency (SCID). The enzyme adenosine deaminase is a housekeeping in nature and is involved in purine catabolism by catalyzing irreversible deamination of adenosine and deoxyadenosine. The SCID patients’ immune system is unable to fight off most of the bacterial and fungal infections due to profound lymphopenia (T-B-NK+). About 20% of the SCID patients are genetically homozygous for defective ADA gene. In our study we aimed to find out genetic variant in ADA gene in a family carrying severe combined immune deficiency. Objective in the current study is to unravel and characterize the molecular cause of the patient suffering from by birth SCID.
 METHODOLOGY: In the present study we enrolled a 6-month-old female SCID patient belonging to highly consanguineous Pakistani family. Patient clinical features included repeated chest infection with failure to thrive, fever and chronic diarrhea. Whole blood samples from patient, parents and healthy siblings were acquired in EDTA tubes. DNA was extracted from all the blood samples.
 RESULTS: Flowcytometry revealed lymphopenia (T-B-NK+) type of SCID. Whole Exome Sequencing (WES) identified a one nucleotide change (c.716G>A) in ADA gene exon 8. The segregation of the identified variant in the family was confirmed through Sanger Sequencing.
 CONCLUSION: In this study, we presented detailed clinical and genetic description of patient suffering from severe combined immune deficiency. The immunological and genetic findings presented in this study will facilitate early diagnosis of the disease. Segregation of the identified variant in the family members will also aid in genetic counseling the family.

A Role for Adenosine Deaminase in Drosophila Larval Development

Adenosine deaminase (ADA) is an enzyme present in all organisms that catalyzes the irreversible deamination of adenosine and deoxyadenosine to inosine and deoxyinosine. Both adenosine and deoxyadenosine are biologically active purines that can have a deep impact on cellular physiology; notably, ADA deficiency in humans causes severe combined immunodeficiency. We have established a Drosophila model to study the effects of altered adenosine levels in vivo by genetic elimination of adenosine deaminase-related growth factor-A (ADGF-A), which has ADA activity and is expressed in the gut and hematopoietic organ. Here we show that the hemocytes (blood cells) are the main regulator of adenosine in the Drosophila larva, as was speculated previously for mammals. The elevated level of adenosine in the hemolymph due to lack of ADGF-A leads to apparently inconsistent phenotypic effects: precocious metamorphic changes including differentiation of macrophage-like cells and fat body disintegration on one hand, and delay of development with block of pupariation on the other. The block of pupariation appears to involve signaling through the adenosine receptor (AdoR), but fat body disintegration, which is promoted by action of the hemocytes, seems to be independent of the AdoR. The existence of such an independent mechanism has also been suggested in mammals.

Adenosine Deaminase-deficient Mice Generated Using a Two-stage Genetic Engineering Strategy Exhibit a Combined Immunodeficiency

Adenosine deaminase (ADA) deficiency in humans leads to a combined immunodeficiency. The mechanisms involved in the lymphoid specificity of the disease are not fully understood due to the inaccessibility of human tissues for detailed analysis and the absence of an adequate animal model for the disease. We report the use of a two-stage genetic engineering strategy to generate ADA-deficient mice that retain many features associated with ADA deficiency in humans, including a combined immunodeficiency. Severe T and B cell lymphopenia was accompanied by a pronounced accumulation of 2'-deoxyadenosine and dATP in the thymus and spleen, and a marked inhibition of S-adenosylhomocysteine hydrolase in these organs. Accumulation of adenosine was widespread among all tissues examined. ADA-deficient mice also exhibited severe pulmonary insufficiency, bone abnormalities, and kidney pathogenesis. These mice have provided in vivo information into the metabolic basis for the immune phenotype associated with ADA deficiency.

Regulation and Function of Adenosine Deaminase in Mice

Publisher Summary Adenosine deaminase (ADA) is an essential and widely distributed enzyme of purine catabolism that catalyzes the hydrolytic deamination of adenosine and deoxyadenosine to inosine and deoxyinosine. The catalytic moiety of ADA exists as a single polypeptide chain, with approximately 83.1% amino-acid sequence identity between humans and mice. Recombinant murine ADA has been subjected to crystallographic analysis and the architecture of the enzyme is a parallel α/β barrel with eight central β strands and eight peripheral α helixes. The importance of ADA for vertebrate systems stems primarily from the physiological impact of its substrates— adenosine and deoxyadenosine. Adenosine functions as an extracellular signal transducer that mediates a large variety of physiological effects by binding to adenosine receptors present on the surface of target cells. Depending on the severity of mutation, ADA deficiency in humans is associated with mild to severe immunodeficiency that, in severe cases, can lead to infant mortality if not treated. ADA is an essential enzyme of purine metabolism that is ubiquitously expressed and displays enhanced expression in specific tissues during development and in the adult.

Evidence for distinct catabolic pathways of adenine ribonucleotides and deoxyribonucleotides in human T lymphoblastoid cells.

The catabolisms of deoxy-ATP and ATP were compared in cultured human T lymphoblastoid cells incubated under various conditions. It was found that in the presence of deoxycoformycin, an inhibitor of adenosine deaminase, deoxyadenosine was the only product of deoxy-ATP catabolism. In contrast, the main products of ATP catabolism in either the presence or the absence of deoxycoformycin were inosine and hypoxanthine. These results demonstrate that deoxy-ATP catabolism proceeds exclusively via deoxyadenosine deamination, whereas ATP catabolism proceeds mainly via adenylate deamination. These findings thus provide an explanation for the selective deoxynucleotide metabolic abnormalities associated with adenosine deaminase deficiency in humans.

The adenosine-like effect of exogenous cyclic AMP upon nucleotide and PP-ribose-P concentrations of cultured human lymphoblasts

FEBS LettersVolume 66, Issue 1 p. 102-106 Full-length articleFree Access The adenosine-like effect of exogenous cyclic AMP upon nucleotide and PP-ribose-P concentrations of cultured human lymphoblasts Floyd F. Snyder, Floyd F. Snyder Division or Rheumatology, Department of Medicine, University of California, San Diego, La Jolla, California, 92093 USASearch for more papers by this authorJ.Edwin Seegmiller, J.Edwin Seegmiller Division or Rheumatology, Department of Medicine, University of California, San Diego, La Jolla, California, 92093 USASearch for more papers by this author Floyd F. Snyder, Floyd F. Snyder Division or Rheumatology, Department of Medicine, University of California, San Diego, La Jolla, California, 92093 USASearch for more papers by this authorJ.Edwin Seegmiller, J.Edwin Seegmiller Division or Rheumatology, Department of Medicine, University of California, San Diego, La Jolla, California, 92093 USASearch for more papers by this author First published: July 01, 1976 https://doi.org/10.1016/0014-5793(76)80595-9Citations: 48AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL References 1 H. Hilz, A. Tarnowski, Biochem. Biophys. Res. Comm., 40, (1970), 973– 981. 2 E. Kaukel, V. Fuhrmann, H. Hilz, Biochem. Biophys. Res. Comm., 48, (1972), 1516– 1524. 3 H. Hilz, E. Kaukel, Mol. Cell. Biochem., 1, (1973), 229– 239. 4 S.S. Solomon, J.S. Brush, A.E. Kitabchi, Science, 169, (1970), 387– 388. 5 B.A. Roller, K. Hirai, V. Defendi, Biochim. Biophys. Acta, 366, (1972), 402– 410. 6 E. Kaukel, H. Hilz, Biochem. Biophys. Res. Comm., 46, (1972), 1011– 1018. 7 D.K. Granner, L. Sellers, A. Lee, C. Butters, L. Kutina, Arch. Biochem. Biophys., 169, (1975), 601– 615. 8 J. Taylor-Papadimitriou, T. Karemfyllis, A. Eukarpidou, G. Karamanlidou, J. Cell. Sci., 19, (1975), 305– 313. 9 W.D. Yushok, J. Biol. Chem., 246, (1971), 1607– 1617. 10 F.F. Snyder, J.F. Henderson, Can. J. Biochem., 51, (1973), 943– 948. 11 H. Green, T.-S. Chan, Science, 182, (1973), 836– 837. 12 E.R. Giblett, J.E. Anderson, F. Cohen, B. Pollara, H.J. Meuwissen, Lancet, 2, (1972), 1067– 1069. 13 J.E. Lever, G. Nuki, J.E. Seegmiller, Proc. Nat. Acad. Sci., 71, (1974), 2679– 2683. 14 K.H. Astrin, Ph. D. Thesis (1973), University of California San Diego 15 F.F. Snyder, J.F. Henderson, S.C. Kim, A.R.P. Paterson, L.W. Brox, Cancer Res., 33, (1973), 2425– 2430. 16 M. Smith, G.I. Drummond, H.G. Khorana, J. Amer. Chem. Soc., 83, (1961), 698– 706. 17 F.F. Snyder, J.F. Henderson, J. Biol. Chem., 248, (1973), 5899– 5904. 18 J.F. Henderson, M.K.Y. Khoo, J. Biol. Chem., 240, (1965), 2349– 2357. 19 A. Hershko, A. Razin, J. Mager, Biochim. Biophys. Acta, 184, (1969), 64– 76. 20 W.R.A. Osborne, N. Spencer, Biochem. J., 133, (1973), 117– 123. 21 R.P. Agarwal, S.M. Sagar, R.E. Parks Jr., Biochem. Pharmacol., 24, (1975), 693– 701. 22 D.E. Atkinson, Biochemistry, 7, (1968), 4030– 4034. 23 H.J. Schaeffer, C.F. Schwender, J. Med. Chem., 17, (1974), 6– 8. 24 C.M. Smith, L.J. Fontenelle, M. Lalanne, J.F. Henderson, Cancer Res., 34, (1974), 463– 467. 25 G. Tyrsted, A.C. Sartorelli, Biochim. Biophys. Acta, 155, (1968), 619– 622. Citing Literature Volume66, Issue1July 01, 1976Pages 102-106 ReferencesRelatedInformation