Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/32797
Title: Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy.
Austin Authors: Khoshkhoo, Sattar;Wang, Yilan;Chahine, Yasmine;Erson-Omay, E Zeynep;Robert, Stephanie M;Kiziltug, Emre;Damisah, Eyiyemisi C;Nelson-Williams, Carol;Zhu, Guangya;Kong, Wenna;Huang, August Yue;Stronge, Edward;Phillips, H Westley;Chhouk, Brian H;Bizzotto, Sara;Chen, Ming Hui;Adikari, Thiuni N;Ye, Zimeng;Witkowski, Tom ;Lai, Dulcie;Lee, Nadine;Lokan, Julie ;Scheffer, Ingrid E ;Berkovic, Samuel F ;Haider, Shozeb;Hildebrand, Michael S ;Yang, Edward;Gunel, Murat;Lifton, Richard P;Richardson, R Mark;Blümcke, Ingmar;Alexandrescu, Sanda;Huttner, Anita;Heinzen, Erin L;Zhu, Jidong;Poduri, Annapurna;DeLanerolle, Nihal;Spencer, Dennis D;Lee, Eunjung Alice;Walsh, Christopher A;Kahle, Kristopher T
Affiliation: Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.;Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts.;
Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts.
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts.
Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts.;Broad Institute of MIT and Harvard, Cambridge, Massachusetts.;Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
Harvard Medical School, Boston, Massachusetts.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles.
Sorbonne University, Paris Brain Institute (ICM), National Institute of Health and Medical Research (INSERM), National Center for Scientific Research (CNRS), Paris, France.
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts.
Medicine (University of Melbourne)
Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill.
Anatomical Pathology
Neurology
Comprehensive Epilepsy Program
Department of Pharmaceutical and Biological Chemistry, University College London School of Pharmacy, London, United Kingdom.
Murdoch Children's Research Institute, Parkville, Australia.
Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut.
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.;Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, New York.
Department of Neurosurgery, Massachusetts General Hospital, Boston.
Department of Neuropathology, University Hospitals Erlangen, Erlangen, Germany.;Epilepsy Center, Cleveland Clinic, Cleveland, Ohio.
Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill.;Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill.
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
Epilepsy Genetics Program, Division of Epilepsy and Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut.
Issue Date: 1-Jun-2023
Date: 2023
Publication information: JAMA neurology 2023-06-01; 80(6)
Abstract: Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown. To test the association between pathogenic somatic variants in the hippocampus and MTLE. This case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy-associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022. Drug-resistant MTLE. Presence and abundance of pathogenic somatic variants in the hippocampus vs the unaffected temporal neocortex. Of 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years; of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippocampus relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] vs 0.3 [0-0.9]; P = .01) were detected in patients with MTLE but not in controls. Ten of these variants were in PTPN11, SOS1, KRAS, BRAF, and NF1, all predicted to constitutively activate Ras/Raf/mitogen-activated protein kinase (MAPK) signaling. Immunohistochemical studies of variant-positive hippocampal tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the PTPN11 variants as a possible dominant gain-of-function mechanism. Hippocampal somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery.
URI: https://ahro.austin.org.au/austinjspui/handle/1/32797
DOI: 10.1001/jamaneurol.2023.0473
ORCID: 
Journal: JAMA Neurology
PubMed URL: 37126322
ISSN: 2168-6157
Type: Journal Article
Appears in Collections:Journal articles

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