A novel class of somatic mutations in blood detected preferentially in CD8+cells

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Valori , M , Jansson , L , Kiviharju , A , Ellonen , P , Rajala , H , Awad , S , Mustjoki , S & Tienari , P J L 2017 , ' A novel class of somatic mutations in blood detected preferentially in CD8+cells ' , Clinical Immunology , vol. 175 , pp. 75-81 . https://doi.org/10.1016/j.clim.2016.11.018

Title: A novel class of somatic mutations in blood detected preferentially in CD8+cells
Author: Valori, Miko; Jansson, Lilja; Kiviharju, Anna; Ellonen, Pekka; Rajala, Hanna; Awad, Shady; Mustjoki, Satu; Tienari, Pentti J. l
Contributor: University of Helsinki, Research Programme for Molecular Neurology
University of Helsinki, Neurologian yksikkö
University of Helsinki, Research Programs Unit
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Clinicum
University of Helsinki, Medicum
University of Helsinki, Medicum
University of Helsinki, Clinicum
Date: 2017-02
Language: eng
Number of pages: 7
Belongs to series: Clinical Immunology
ISSN: 1521-6616
URI: http://hdl.handle.net/10138/193265
Abstract: Somatic mutations have a central role in cancer but their role in other diseases such as autoimmune disorders is poorly understood. Earlier work has provided indirect evidence of rare somatic mutations in autoreactive T-lymphocytes in multiple sclerosis (MS) patients but such mutations have not been identified thus far. We analysed somatic mutations in blood in 16 patients with relapsing MS and 4 with other neurological autoimmune disease. To facilitate the detection of somatic mutations CD4 +, CD8 +, CD19 + and CD4-/CD8-/CD19- cell subpopulations were separated. We performed next-generation DNA sequencing targeting 986 immune related genes. Somatic mutations were called by comparing the sequence data of each cell subpopulation to other subpopulations of the same patient and validated by amplicon sequencing. We found non-synonymous somatic mutations in 12 (60%) patients (10 MS, 1 myasthenia gravis, 1 narcolepsy). There were 27 mutations, all different and mostly novel (67%). They were discovered at subpopulation-wise allelic fractions of 0.2%-4.6% (median 0.95%). Multiple mutations were found in 8 patients. The mutations were enriched in CD8 + cells (85% of mutations). In follow-up after a median time of 2.3 years, 96% of the mutations were still detectable. These results unravel a novel class of persistent somatic mutations, many of which were in genes that may play a role in autoimmunity (ATM, BTK, CD46, CD180, CLIP2, HMMR, IKEF3, ITGB3, KIR3DL2, MAPK10, CD56/NCAM1, RBM6, RORA, RPM and STAT3). Whether some of this class of mutations plays a role in disease is currently unclear, but these results define an interesting hitherto unknown research target for future studies. (C) 2016 The Authors. Published by Elsevier Inc.
Subject: Somatic mutation
Autoimmune disease
Multiple sclerosis
3121 General medicine, internal medicine and other clinical medicine

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