Aicardi-Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity
Open accessAbstract
Aicardi-Goutières syndrome (AGS) is a genetically determined encephalopathy demonstrating phenotypic overlap both with the sequelae of congenital infection and with systemic lupus erythematosus (SLE). Recent molecular advances have revealed that AGS can be caused by mutations in any one of five genes, most commonly on a recessive basis but occasionally as a dominant trait. Like AGS, SLE is associated with a perturbation of type I interferon metabolism. Interestingly then, heterozygous mutations in the AGS1 gene TREX1 underlie a cutaneous subtype of SLE-called familial chilblain lupus, and mutations in TREX1 represent the single most common cause of monogenic SLE identified to date. Evidence is emerging to show that the nucleases defective in AGS are involved in removing endogenously produced nucleic acid (NA) species, and that a failure of this removal results in activation of the immune system. This hypothesis explains the phenotypic overlap of AGS with congenital infection and some aspects of SLE, where an equivalent type I interferon-mediated innate immune response is triggered by viral and self NAs, respectively. The combined efforts of clinicians, geneticists, immunologists and cell biologists are producing rapid progress in the understanding of AGS and overlapping autoimmune disorders. These studies provide important insights into the pathogenesis of SLE and beg urgent questions about the development and use of immunosuppressive therapies in AGS and related phenotypes.
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Studies of human autoimmune or autoinflammatory conditions, including systemic lupus erythematosus (SLE) and Aicardi-Goutières syndrome (AGS), have implicated a number of genes primarily involved in nucleic acid metabolism.
“Studies of human autoimmune or autoinflammatory conditions, including systemic lupus erythematosus (SLE) and the rare Aicardi-Goutières syndrome (AGS) have implicated a number of genes primarily involved in nucleic acid metabolism 27.”
From Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis (2013) · cites this paper as [27]
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- Authors
- Crow, Y. J., & Rehwinkel, J.
- Affiliations
- Manchester Academic Health Science Centre (GB)
- Cancer Research UK (GB)
- Corresponding author
- Crow, Y. J.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-10-06
- Volume
- 18
- Issue
- R2
- Pages
- R130-R136
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC2758706
- OpenAlex
- W2136400402
- Cited by
- 289
- References
- 8
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 8 · 2023: 11 · 2022: 12 · 2021: 18 · 2020: 14 · 2019: 16 · 2018: 13 · 2017: 18 · 2016: 19 · 2015: 29 · 2014: 23 · 2013: 33 · 2012: 24
- FWCI
- 2.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- Wellcome Trust
- Newlife the Charity for Disabled Children
- National Institute for Health and Care Research
- Royal Society
- Manchester Biomedical Research Centre
- Topics
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- Aicardi-Goutières syndrome, systemic lupus erythematosus, TREX1, type I interferon, nucleic acid metabolism, nucleases, autoimmunity, congenital infection, innate immune response, immunosuppressive therapy, genetic mutations
- MeSH terms
- Abnormalities, Multiple, Exodeoxyribonucleases, Humans, Nucleic Acids, Phenotype, Phosphoproteins, Syndrome, Autoimmunity
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