| Autor: |
Inna Tabansky, Akemi J. Tanaka, Jiayao Wang, Guanglan Zhang, Irena Dujmovic, Simone Mader, Venkatesh Jeganathan, Tracey DeAngelis, Michael Funaro, Asaff Harel, Mark Messina, Maya Shabbir, Vishaan Nursey, William DeGouvia, Micheline Laurent, Karen Blitz, Peter Jindra, Mark Gudesblatt, Regeneron Genetics Center, Alejandra King, Jelena Drulovic, Edmond Yunis, Vladimir Brusic, Yufeng Shen, Derin B. Keskin, Souhel Najjar, Joel N. H. Stern |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
Frontiers in Immunology, Vol 13 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
1664-3224 |
| DOI: |
10.3389/fimmu.2022.900605 |
| Popis: |
Neuromyelitis optica spectrum disorders (NMOSD) are rare, debilitating autoimmune diseases of the central nervous system. Many NMOSD patients have antibodies to Aquaporin-4 (AQP4). Prior studies show associations of NMOSD with individual Human Leukocyte Antigen (HLA) alleles and with mutations in the complement pathway and potassium channels. HLA allele associations with NMOSD are inconsistent between populations, suggesting complex relationships between the identified alleles and risk of disease. We used a retrospective case-control approach to identify contributing genetic variants in patients who met the diagnostic criteria for NMOSD and their unaffected family members. Potentially deleterious variants identified in NMOSD patients were compared to members of their families who do not have the disease and to existing databases of human genetic variation. HLA sequences from patients from Belgrade, Serbia, were compared to the frequency of HLA haplotypes in the general population in Belgrade. We analyzed exome sequencing on 40 NMOSD patients and identified rare inherited variants in the complement pathway and potassium channel genes. Haplotype analysis further detected two haplotypes, HLA-A*01, B*08, DRB1*03 and HLA-A*01, B*08, C*07, DRB1*03, DQB1*02, which were more prevalent in NMOSD patients than in unaffected individuals. In silico modeling indicates that HLA molecules within these haplotypes are predicted to bind AQP4 at several sites, potentially contributing to the development of autoimmunity. Our results point to possible autoimmune and neurodegenerative mechanisms that cause NMOSD, and can be used to investigate potential NMOSD drug targets. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
|
