-
Orphanet Journal of Rare Diseases Apr 2018Adenosine deaminase (ADA) deficiency leads to an accumulation of toxic purine degradation by-products, most potently affecting lymphocytes, leading to adenosine... (Review)
Review
Adenosine deaminase (ADA) deficiency leads to an accumulation of toxic purine degradation by-products, most potently affecting lymphocytes, leading to adenosine deaminase-deficient severe combined immunodeficiency. Whilst most notable affects are on lymphocytes, other manifestations include skeletal abnormalities, neurodevelopmental affects and pulmonary manifestations associated with pulmonary-alveolar proteinosis. Affected patients present in early infancy, usually with persistent infection, or with pulmonary insufficiency. Three treatment options are currently available. Initial treatment with enzyme replacement therapy may alleviate acute symptoms and enable partial immunological reconstitution, but treatment is life-long, immune reconstitution is incomplete, and the reconstituted immune system may nullify the effects of the enzyme replacement. Hematopoietic stem cell transplant has long been established as the treatment of choice, particularly where a matched sibling or well matched unrelated donor is available. More recently, the use of gene addition techniques to correct the genetic defect in autologous haematopoietic stem cells treatment has demonstrated immunological and clinical efficacy. This article reviews the biology, clinical presentation, diagnosis and treatment of ADA-deficiency.
Topics: Adenosine Deaminase; Agammaglobulinemia; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Pulmonary Alveolar Proteinosis; Severe Combined Immunodeficiency
PubMed: 29690908
DOI: 10.1186/s13023-018-0807-5 -
International Journal of Cardiology Jun 2016Purines perform many important functions in the cell, being the formation of the monomeric precursors of nucleic acids DNA and RNA the most relevant one. Purines which... (Review)
Review
Purines perform many important functions in the cell, being the formation of the monomeric precursors of nucleic acids DNA and RNA the most relevant one. Purines which also contribute to modulate energy metabolism and signal transduction, are structural components of some coenzymes and have been shown to play important roles in the physiology of platelets, muscles and neurotransmission. All cells require a balanced quantity of purines for growth, proliferation and survival. Under physiological conditions the enzymes involved in the purine metabolism maintain in the cell a balanced ratio between their synthesis and degradation. In humans the final compound of purines catabolism is uric acid. All other mammals possess the enzyme uricase that converts uric acid to allantoin that is easily eliminated through urine. Overproduction of uric acid, generated from the metabolism of purines, has been proven to play emerging roles in human disease. In fact the increase of serum uric acid is inversely associated with disease severity and especially with cardiovascular disease states. This review describes the enzymatic pathways involved in the degradation of purines, getting into their structure and biochemistry until the uric acid formation.
Topics: 5'-Nucleotidase; Adenosine Deaminase; Cardiovascular Diseases; Humans; Metabolic Networks and Pathways; Purines; Uric Acid; Xanthine Dehydrogenase
PubMed: 26316329
DOI: 10.1016/j.ijcard.2015.08.109 -
Science (New York, N.Y.) Aug 2020Bacteria and archaea are frequently attacked by viruses and other mobile genetic elements and rely on dedicated antiviral defense systems, such as restriction...
Bacteria and archaea are frequently attacked by viruses and other mobile genetic elements and rely on dedicated antiviral defense systems, such as restriction endonucleases and CRISPR, to survive. The enormous diversity of viruses suggests that more types of defense systems exist than are currently known. By systematic defense gene prediction and heterologous reconstitution, here we discover 29 widespread antiviral gene cassettes, collectively present in 32% of all sequenced bacterial and archaeal genomes, that mediate protection against specific bacteriophages. These systems incorporate enzymatic activities not previously implicated in antiviral defense, including RNA editing and retron satellite DNA synthesis. In addition, we computationally predict a diverse set of other putative defense genes that remain to be characterized. These results highlight an immense array of molecular functions that microbes use against viruses.
Topics: Adenosine Deaminase; Archaea; Archaeal Proteins; Archaeal Viruses; Bacteria; Bacterial Proteins; Bacteriophages; CRISPR-Cas Systems; Genes, Archaeal; Genes, Bacterial; Protein Domains; RNA Editing
PubMed: 32855333
DOI: 10.1126/science.aba0372 -
Best Practice & Research. Clinical... Mar 2023The deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease caused by loss-of-function (LOF) mutations in the ADA2 gene and was first described in... (Review)
Review
The deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease caused by loss-of-function (LOF) mutations in the ADA2 gene and was first described in 2014. Initially, it was described as vasculopathy/vasculitis that mostly affected infants and young children and closely resembled polyarteritis nodosa (PAN). Skin rash and ischemic/hemorrhagic stroke are predominant symptoms. However, the clinical spectrum of DADA2 has continued to expand since then. It has now been reported in adults as well. Besides vasculitis-related manifestations, hematological, immunological, and autoinflammatory manifestations are now well recognized. More than 100 disease-causing mutations have been described. The decrease in ADA2 enzyme leads to an increased extracellular adenosine level that, in turn, triggers a proinflammatory cascade. The disease is highly variable, and patients carrying same mutation may have different ages of presentation and clinical features. Anti-tumor necrosis factor (TNF) agents are mainstay of treatment of the vasculitis/vasculopathy phenotype. Hematopoietic stem cell transplant (HSCT) has been performed in patients with severe hematological manifestations. Recombinant ADA2 protein and gene therapy hold a promise for future.
Topics: Child; Humans; Child, Preschool; Adenosine Deaminase; Intercellular Signaling Peptides and Proteins; Vasculitis; Polyarteritis Nodosa; Mutation
PubMed: 37328410
DOI: 10.1016/j.berh.2023.101844 -
Molecular Therapy : the Journal of the... Jun 2023RNA therapeutics have had a tremendous impact on medicine, recently exemplified by the rapid development and deployment of mRNA vaccines to combat the COVID-19 pandemic.... (Review)
Review
RNA therapeutics have had a tremendous impact on medicine, recently exemplified by the rapid development and deployment of mRNA vaccines to combat the COVID-19 pandemic. In addition, RNA-targeting drugs have been developed for diseases with significant unmet medical needs through selective mRNA knockdown or modulation of pre-mRNA splicing. Recently, RNA editing, particularly antisense RNA-guided adenosine deaminase acting on RNA (ADAR)-based programmable A-to-I editing, has emerged as a powerful tool to manipulate RNA to enable correction of disease-causing mutations and modulate gene expression and protein function. Beyond correcting pathogenic mutations, the technology is particularly well suited for therapeutic applications that require a transient pharmacodynamic effect, such as the treatment of acute pain, obesity, viral infection, and inflammation, where it would be undesirable to introduce permanent alterations to the genome. Furthermore, transient modulation of protein function, such as altering the active sites of enzymes or the interface of protein-protein interactions, opens the door to therapeutic avenues ranging from regenerative medicine to oncology. These emerging RNA-editing-based toolsets are poised to broadly impact biotechnology and therapeutic applications. Here, we review the emerging field of therapeutic RNA editing, highlight recent laboratory advancements, and discuss the key challenges on the path to clinical development.
Topics: Humans; RNA; RNA-Binding Proteins; RNA Editing; Pandemics; COVID-19; Adenosine Deaminase
PubMed: 36620962
DOI: 10.1016/j.ymthe.2023.01.005 -
Trends in Genetics : TIG Aug 2022The family of adenosine deaminases acting on RNA (ADARs) regulates global gene expression output by catalyzing adenosine-to-inosine (A-to-I) editing of double-stranded... (Review)
Review
The family of adenosine deaminases acting on RNA (ADARs) regulates global gene expression output by catalyzing adenosine-to-inosine (A-to-I) editing of double-stranded RNA (dsRNA) and through interacting with RNA and other proteins. ADARs play important roles in development and disease, including an increasing connection to cancer progression. ADAR1 has demonstrated a largely pro-oncogenic role in a growing list of cancer types, and its function in cancer has been attributed to diverse mechanisms. Here, we review existing literature on ADAR1 biology and function, its roles in human disease including cancer, and summarize known cancer-associated phenotypes and mechanisms. Lastly, we discuss implications and outstanding questions in the field, including strategies for targeting ADAR1 in cancer.
Topics: Adenosine; Adenosine Deaminase; Humans; Neoplasms; RNA Editing; RNA, Double-Stranded; RNA-Binding Proteins
PubMed: 35459560
DOI: 10.1016/j.tig.2022.03.013 -
JAMA Network Open May 2023Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or... (Review)
Review
IMPORTANCE
Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency affecting both children and adults. DADA2 is among the more common monogenic autoinflammatory diseases, with an estimate of more than 35 000 cases worldwide, but currently, there are no guidelines for diagnostic evaluation or management.
OBJECTIVE
To review the available evidence and develop multidisciplinary consensus statements for the evaluation and management of DADA2.
EVIDENCE REVIEW
The DADA2 Consensus Committee developed research questions based on data collected from the International Meetings on DADA2 organized by the DADA2 Foundation in 2016, 2018, and 2020. A comprehensive literature review was performed for articles published prior to 2022. Thirty-two consensus statements were generated using a modified Delphi process, and evidence was graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence.
FINDINGS
The DADA2 Consensus Committee, comprising 3 patient representatives and 35 international experts from 18 countries, developed consensus statements for (1) diagnostic testing, (2) screening, (3) clinical and laboratory evaluation, and (4) management of DADA2 based on disease phenotype. Additional consensus statements related to the evaluation and treatment of individuals with DADA2 who are presymptomatic and carriers were generated. Areas with insufficient evidence were identified, and questions for future research were outlined.
CONCLUSIONS AND RELEVANCE
DADA2 is a potentially fatal disease that requires early diagnosis and treatment. By summarizing key evidence and expert opinions, these consensus statements provide a framework to facilitate diagnostic evaluation and management of DADA2.
Topics: Adenosine Deaminase; Intercellular Signaling Peptides and Proteins; Phenotype; Heterozygote
PubMed: 37256629
DOI: 10.1001/jamanetworkopen.2023.15894 -
Wiley Interdisciplinary Reviews. RNA Jan 2022Adenosine deaminase acting on RNA (ADAR) catalyzes the posttranscriptional conversion of adenosine to inosine in double-stranded RNA (dsRNA), which can lead to the... (Review)
Review
Adenosine deaminase acting on RNA (ADAR) catalyzes the posttranscriptional conversion of adenosine to inosine in double-stranded RNA (dsRNA), which can lead to the creation of missense mutations in coding sequences. Recent studies show that editing-dependent functions of ADAR1 protect dsRNA from dsRNA-sensing molecules and inhibit innate immunity and the interferon-mediated response. Deficiency in these ADAR1 functions underlie the pathogenesis of autoinflammatory diseases such as the type I interferonopathies Aicardi-Goutieres syndrome and dyschromatosis symmetrica hereditaria. ADAR1-mediated editing of endogenous coding and noncoding RNA as well as ADAR1 editing-independent interactions with DICER can also have oncogenic or tumor suppressive effects that affect tumor proliferation, invasion, and response to immunotherapy. The combination of proviral and antiviral roles played by ADAR1 in repressing the interferon response and editing viral RNAs alters viral morphogenesis and cell susceptibility to infection. This review analyzes the structure and function of ADAR1 with a focus on its position in human disease pathways and the mechanisms of its disease-associated effects. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > RNA Editing and Modification RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.
Topics: Adenosine Deaminase; Autoimmune Diseases of the Nervous System; Humans; Inosine; Nervous System Malformations; RNA Editing; RNA, Double-Stranded; RNA-Binding Proteins
PubMed: 34105255
DOI: 10.1002/wrna.1665 -
Nature Jul 2022The RNA-editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) limits the accumulation of endogenous immunostimulatory double-stranded RNA (dsRNA). In humans,...
The RNA-editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) limits the accumulation of endogenous immunostimulatory double-stranded RNA (dsRNA). In humans, reduced ADAR1 activity causes the severe inflammatory disease Aicardi-Goutières syndrome (AGS). In mice, complete loss of ADAR1 activity is embryonically lethal, and mutations similar to those found in patients with AGS cause autoinflammation. Mechanistically, adenosine-to-inosine (A-to-I) base modification of endogenous dsRNA by ADAR1 prevents chronic overactivation of the dsRNA sensors MDA5 and PKR. Here we show that ADAR1 also inhibits the spontaneous activation of the left-handed Z-nucleic acid sensor ZBP1. Activation of ZBP1 elicits caspase-8-dependent apoptosis and MLKL-mediated necroptosis of ADAR1-deficient cells. ZBP1 contributes to the embryonic lethality of Adar-knockout mice, and it drives early mortality and intestinal cell death in mice deficient in the expression of both ADAR and MAVS. The Z-nucleic-acid-binding Zα domain of ADAR1 is necessary to prevent ZBP1-mediated intestinal cell death and skin inflammation. The Zα domain of ADAR1 promotes A-to-I editing of endogenous Alu elements to prevent dsRNA formation through the pairing of inverted Alu repeats, which can otherwise induce ZBP1 activation. This shows that recognition of Alu duplex RNA by ZBP1 may contribute to the pathological features of AGS that result from the loss of ADAR1 function.
Topics: Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Deaminase; Animals; Apoptosis; Autoimmune Diseases of the Nervous System; Caspase 8; Humans; Inflammation; Inosine; Intestines; Mice; Necroptosis; Nervous System Malformations; RNA Editing; RNA, Double-Stranded; RNA-Binding Proteins; Skin
PubMed: 35859175
DOI: 10.1038/s41586-022-04974-w -
Cell Mar 2023RADAR is a two-protein bacterial defense system that was reported to defend against phage by "editing" messenger RNA. Here, we determine cryo-EM structures of the RADAR...
RADAR is a two-protein bacterial defense system that was reported to defend against phage by "editing" messenger RNA. Here, we determine cryo-EM structures of the RADAR defense complex, revealing RdrA as a heptameric, two-layered AAA+ ATPase and RdrB as a dodecameric, hollow complex with twelve surface-exposed deaminase active sites. RdrA and RdrB join to form a giant assembly up to 10 MDa, with RdrA docked as a funnel over the RdrB active site. Surprisingly, our structures reveal an RdrB active site that targets mononucleotides. We show that RdrB catalyzes ATP-to-ITP conversion in vitro and induces the massive accumulation of inosine mononucleotides during phage infection in vivo, limiting phage replication. Our results define ATP mononucleotide deamination as a determinant of RADAR immunity and reveal supramolecular assembly of a nucleotide-modifying machine as a mechanism of anti-phage defense.
Topics: Bacteriophages; Cryoelectron Microscopy; ATPases Associated with Diverse Cellular Activities; Adenosine Triphosphate; Adenosine Deaminase
PubMed: 36764290
DOI: 10.1016/j.cell.2023.01.012