TY - JOUR
T1 - Brain molecular mechanisms in Rasmussen encephalitis
AU - Leitner, Dominique F.
AU - Lin, Ziyan
AU - Sawaged, Zacharia
AU - Kanshin, Evgeny
AU - Friedman, Daniel
AU - Devore, Sasha
AU - Ueberheide, Beatrix
AU - Chang, Julia W.
AU - Mathern, Gary W.
AU - Anink, Jasper J.
AU - Aronica, Eleonora
AU - Wisniewski, Thomas
AU - Devinsky, Orrin
N1 - Funding Information: Funding was provided by FACES (Finding a Cure for Epilepsy and Seizures), the Rasmussen Encephalitis Children's Project, and the National Institutes of Health (P01AG060882 and P30AG066512). Gilad Evrony provided access to Qiagen Clinical Insight. Funding Information: The authors report no conflicts of interest. D.F. receives salary support for consulting and clinical trial‐related activities performed on behalf of the Epilepsy Study Consortium, a nonprofit organization. D.F. receives no personal income for these activities. New York University receives a fixed amount from the Epilepsy Study Consortium toward D.F.'s salary. Within the past 2 years, the Epilepsy Study Consortium has received payments for research services performed by D.F. from Alterity, Baergic, Biogen, BioXcell, Cerevel, Cerebral, Jannsen, Lundbeck, Neurocrine, SK Life Science, and Xenon. He has also served as a paid consultant for Neurelis Pharmaceuticals and Receptor Life Sciences. He has received research support from NINDS, CDC, Epitel, and Neuropace unrelated to this study. He holds equity interests in Neuroview Technology. He received royalty income from Oxford University Press. S.D. receives salary support from the National Institutes of Health, Department of Defense, and Templeton World Charity Foundation unrelated to this study. Publisher Copyright: © 2022 International League Against Epilepsy.
PY - 2022
Y1 - 2022
N2 - Objective: This study was undertaken to identify molecular mechanisms in brain tissue of Rasmussen encephalitis (RE) when compared to people with non-RE epilepsy (PWE) and control cases using whole exome sequencing (WES), RNAseq, and proteomics. Methods: Frozen brain tissue (ages = 2–19 years) was obtained from control autopsy (n = 14), surgical PWE (n = 10), and surgical RE cases (n = 27). We evaluated WES variants in RE associated with epilepsy, seizures, RE, and human leukocyte antigens (HLAs). Differential expression was evaluated by RNAseq (adjusted p <.05) and label-free quantitative mass spectrometry (false discovery rate < 5%) in the three groups. Results: WES revealed no common pathogenic variants in RE, but several rare and likely deleterious variants of unknown significance (VUS; ANGPTL7/MTOR, SCN1A, FCGR3B, MTOR) and more common HLA VUS in >25% of RE cases (HLA-DRB1, HLA-DQA2), all with allele frequency < 5% in the general population. RNAseq in RE versus PWE (1516 altered transcripts) revealed significant activation of crosstalk between dendritic and natural killer cells (p = 7.94 × 10−6, z = 2.65), in RE versus control (7466 transcripts) neuroinflammation signaling activation (p = 6.31 × 10−13, z = 5.07), and in PWE versus control (945 transcripts) phagosome formation activation (p = 2.00 × 10−13, z = 5.61). Proteomics detected fewer altered targets. Significance: In RE, we identified activated immune signaling pathways and immune cell type annotation enrichment that suggest roles of the innate and adaptive immune responses, as well as HLA variants that may increase vulnerability to RE. Follow-up studies could evaluate cell type density and subregional localization associated with top targets, clinical history (neuropathology, disease duration), and whether modulating crosstalk between dendritic and natural killer cells may limit disease progression.
AB - Objective: This study was undertaken to identify molecular mechanisms in brain tissue of Rasmussen encephalitis (RE) when compared to people with non-RE epilepsy (PWE) and control cases using whole exome sequencing (WES), RNAseq, and proteomics. Methods: Frozen brain tissue (ages = 2–19 years) was obtained from control autopsy (n = 14), surgical PWE (n = 10), and surgical RE cases (n = 27). We evaluated WES variants in RE associated with epilepsy, seizures, RE, and human leukocyte antigens (HLAs). Differential expression was evaluated by RNAseq (adjusted p <.05) and label-free quantitative mass spectrometry (false discovery rate < 5%) in the three groups. Results: WES revealed no common pathogenic variants in RE, but several rare and likely deleterious variants of unknown significance (VUS; ANGPTL7/MTOR, SCN1A, FCGR3B, MTOR) and more common HLA VUS in >25% of RE cases (HLA-DRB1, HLA-DQA2), all with allele frequency < 5% in the general population. RNAseq in RE versus PWE (1516 altered transcripts) revealed significant activation of crosstalk between dendritic and natural killer cells (p = 7.94 × 10−6, z = 2.65), in RE versus control (7466 transcripts) neuroinflammation signaling activation (p = 6.31 × 10−13, z = 5.07), and in PWE versus control (945 transcripts) phagosome formation activation (p = 2.00 × 10−13, z = 5.61). Proteomics detected fewer altered targets. Significance: In RE, we identified activated immune signaling pathways and immune cell type annotation enrichment that suggest roles of the innate and adaptive immune responses, as well as HLA variants that may increase vulnerability to RE. Follow-up studies could evaluate cell type density and subregional localization associated with top targets, clinical history (neuropathology, disease duration), and whether modulating crosstalk between dendritic and natural killer cells may limit disease progression.
KW - RNAseq
KW - Rasmussen encephalitis
KW - exome
KW - proteomics
UR - http://www.scopus.com/inward/record.url?scp=85142438712&partnerID=8YFLogxK
U2 - https://doi.org/10.1111/epi.17457
DO - https://doi.org/10.1111/epi.17457
M3 - Article
C2 - 36336987
SN - 0013-9580
JO - Epilepsia
JF - Epilepsia
ER -