How (Ultra‐)Rare Gene Variants Improve Our Understanding of More Common Autoimmune and Inflammatory Diseases
The aim of this study was to explore the impact of rare and ultra‐rare genetic variants on the understanding and treatment of autoimmune and autoinflammatory diseases with a focus on systemic lupus erythematosus (SLE) and Behçet syndrome. This review summarizes current research on the monogenic caus...
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| Format: | Article |
| Language: | English |
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Wiley
2025-02-01
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| Series: | ACR Open Rheumatology |
| Online Access: | https://doi.org/10.1002/acr2.70003 |
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| author | Alexandre Belot Maud Tusseau Jade Cognard Sophie Georgin‐Lavialle Guilaine Boursier Christian M. Hedrich |
| author_facet | Alexandre Belot Maud Tusseau Jade Cognard Sophie Georgin‐Lavialle Guilaine Boursier Christian M. Hedrich |
| author_sort | Alexandre Belot |
| collection | DOAJ |
| description | The aim of this study was to explore the impact of rare and ultra‐rare genetic variants on the understanding and treatment of autoimmune and autoinflammatory diseases with a focus on systemic lupus erythematosus (SLE) and Behçet syndrome. This review summarizes current research on the monogenic causes of SLE and Behçet syndrome, highlighting the various pathways that can be responsible for these unique phenotypes. In monogenic SLE, the identification of complement and DNASE1L3 deficiencies has elucidated mechanisms of apoptotic body accumulation and extracellular nucleic acid sensing. Type I interferonopathies underline the specific role of DNA/RNA sensing and the interferon overexpression in the development of systemic autoimmunity. Other significant genetic defects include Toll‐like receptor hypersignaling and JAK/STATopathies, which contribute to the breakdown of immune tolerance. To date, genetic defects directly affecting B and T cell biology only account for a minority of identified causes of monogenic lupus, highlighting the importance of a tight regulation of mechanistic target of rapamycin and RAS (Rat sarcoma GTPase)/MAPK (mitogen‐activated protein kinase) signaling in lupus. In Behçet syndrome, rare variants in TNFAIP3, RELA, and NFKB1 genes have been identified, underscoring the importance of NF‐κB overactivation. Additional monogenic diseases such as ELF4, WDR1 mutations and trisomy 8 further illustrate the genetic complexity of this condition. Observations from genetic studies in SLE and Behçet syndrome highlight the complexity of systemic inflammatory diseases in which distinct molecular defects caused by single‐gene mutations can promote lupus or Behçet syndromes, often unrecognizable from their genetically complex “classical” forms. Insights gained from studying rare genetic variants enhance our understanding of immune function in health and disease, paving the way for targeted therapies and personalized medicine. |
| format | Article |
| id | doaj-art-dca96a08ae7045e18e09d98703f564d3 |
| institution | DOAJ |
| issn | 2578-5745 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | ACR Open Rheumatology |
| spelling | doaj-art-dca96a08ae7045e18e09d98703f564d32025-08-20T03:11:24ZengWileyACR Open Rheumatology2578-57452025-02-0172n/an/a10.1002/acr2.70003How (Ultra‐)Rare Gene Variants Improve Our Understanding of More Common Autoimmune and Inflammatory DiseasesAlexandre Belot0Maud Tusseau1Jade Cognard2Sophie Georgin‐Lavialle3Guilaine Boursier4Christian M. Hedrich5Centre International de Recherche en Infectiologie, University of Lyon, Inserm U1111, Université Claude Bernard Lyon 1, Centre National de la Recherche Scientifique, UMR5308, École normale supérieure de Lyon, National Referee Centre for Rheumatic and Autoimmune and Systemic Diseases in Children, and Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Lyon, France, and French National Reference Center of Autoinflammatory Diseases and Amyloidosis Lyon FranceCentre International de Recherche en Infectiologie, University of Lyon, Inserm U1111, Université Claude Bernard Lyon 1, Centre National de la Recherche Scientifique, UMR5308, École normale supérieure de Lyon, National Referee Centre for Rheumatic and AutoImmune and Systemic Diseases in Children, and Hôpital Femme Mère Enfant and Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France, and French National Reference Center of Autoinflammatory Diseases and Amyloidosis Paris FranceAmerican Memorial Hospital, Centre Hospitalier Universitaire Reims, Reims Champagne‐Ardenne University Reims FranceFrench National Reference Center of Autoinflammatory Diseases and Amyloidosis, Paris, France, and Sorbonne Université, Hôpital Tenon, DMU 3ID, AP‐HP Paris FranceFrench National Reference Center of Autoinflammatory Diseases and Amyloidosis, Paris, France, and Centre Hospitalier Universitaire Montpellier, University of Montpellier Montpellier FranceInstitute of Life Course and Medical Sciences, University of Liverpool and Alder Hey Children's NHS Foundation Trust Liverpool United KingdomThe aim of this study was to explore the impact of rare and ultra‐rare genetic variants on the understanding and treatment of autoimmune and autoinflammatory diseases with a focus on systemic lupus erythematosus (SLE) and Behçet syndrome. This review summarizes current research on the monogenic causes of SLE and Behçet syndrome, highlighting the various pathways that can be responsible for these unique phenotypes. In monogenic SLE, the identification of complement and DNASE1L3 deficiencies has elucidated mechanisms of apoptotic body accumulation and extracellular nucleic acid sensing. Type I interferonopathies underline the specific role of DNA/RNA sensing and the interferon overexpression in the development of systemic autoimmunity. Other significant genetic defects include Toll‐like receptor hypersignaling and JAK/STATopathies, which contribute to the breakdown of immune tolerance. To date, genetic defects directly affecting B and T cell biology only account for a minority of identified causes of monogenic lupus, highlighting the importance of a tight regulation of mechanistic target of rapamycin and RAS (Rat sarcoma GTPase)/MAPK (mitogen‐activated protein kinase) signaling in lupus. In Behçet syndrome, rare variants in TNFAIP3, RELA, and NFKB1 genes have been identified, underscoring the importance of NF‐κB overactivation. Additional monogenic diseases such as ELF4, WDR1 mutations and trisomy 8 further illustrate the genetic complexity of this condition. Observations from genetic studies in SLE and Behçet syndrome highlight the complexity of systemic inflammatory diseases in which distinct molecular defects caused by single‐gene mutations can promote lupus or Behçet syndromes, often unrecognizable from their genetically complex “classical” forms. Insights gained from studying rare genetic variants enhance our understanding of immune function in health and disease, paving the way for targeted therapies and personalized medicine.https://doi.org/10.1002/acr2.70003 |
| spellingShingle | Alexandre Belot Maud Tusseau Jade Cognard Sophie Georgin‐Lavialle Guilaine Boursier Christian M. Hedrich How (Ultra‐)Rare Gene Variants Improve Our Understanding of More Common Autoimmune and Inflammatory Diseases ACR Open Rheumatology |
| title | How (Ultra‐)Rare Gene Variants Improve Our Understanding of More Common Autoimmune and Inflammatory Diseases |
| title_full | How (Ultra‐)Rare Gene Variants Improve Our Understanding of More Common Autoimmune and Inflammatory Diseases |
| title_fullStr | How (Ultra‐)Rare Gene Variants Improve Our Understanding of More Common Autoimmune and Inflammatory Diseases |
| title_full_unstemmed | How (Ultra‐)Rare Gene Variants Improve Our Understanding of More Common Autoimmune and Inflammatory Diseases |
| title_short | How (Ultra‐)Rare Gene Variants Improve Our Understanding of More Common Autoimmune and Inflammatory Diseases |
| title_sort | how ultra rare gene variants improve our understanding of more common autoimmune and inflammatory diseases |
| url | https://doi.org/10.1002/acr2.70003 |
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