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TPP2 mutation associated with sterile brain inflammation mimicking MS
Eva M Reinthaler1, Elisabeth Graf1, Tobias Zrzavy1
1Department of Neurology (E.M.R., S.P., C.S., F.L., F.Z., A.Z.), Medical University of Vienna, Austria; Institut für Humangenetik (E.G., T.W., T.S.), Helmholtz Zentrum München, Germany; Center for Brain Research (T.Z., H.L.), Medical University of Vienna; Division of Nephrology and Dialysis (C.K.), Department of Internal Medicine III, Medical University of Vienna; Department of Physical Medicine (M.K.), Rehabilitation and Occupational Medicine, Medical University of Vienna, Austria; Lübeck Interdisciplinary Platform for Genome Analytics (C.M.L.), Institutes of Neurogenetics and for Cardiogenetics, University of Lübeck; Department of Neurology and Neuroimaging Center (NIC) (C.M.L.), Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University Mainz; Department of Human Genetics (S.H., J.T.E.), Ruhr-University Bochum; Herdecke (J.T.E.), ZBAF, Faculty of Health, University Witten; Department of Neurology (U.K.Z., M.H.), Neuroimmunological Section, University of Rostock; Department of Neurology (A.D.), Department of Clinical Genomics (A.D.), Department of Neuroscience (A.D.), Jeweils Mayo Clinic, Jacksonville, FL; Department of Neurology (S.G.M.), University of Muenster, Germany; Department of Physiology and Biochemistry (M.A., B.M.), School of Medicine, the University of Jordan; The National Center (Institute) for Diabetes (M.E.-K.), Endocrinology and Genetics (NCDEG), Amman, Jordan; Department of Medical Genetics (C.V.-G., A.D.S.), University of British Columbia, Vancouver, Canada; Department of Medical Biochemistry and Microbiology (B.T.), Uppsala University, Sweden; Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders (W.K.), SMZ-Ost-Donauspital, Vienna, Austria; and Institute for Neuroimmunological and Neurodegenerative Disorders (W.K.), SMZ-Ost-Donauspital, Vienna, Austria.
A genetic mutation in the tripeptidyl peptidase II (TPP2) gene caused sterile brain inflammation in a Syrian family. This finding suggests TPP2 may have a broader role in multiple sclerosis (MS) inflammation.
Area of Science:
- Genetics
- Neuroimmunology
- Biochemistry
Background:
- Sterile brain inflammation can mimic multiple sclerosis (MS).
- Consanguineous families are valuable for identifying genetic causes of rare diseases.
Purpose of the Study:
- To identify the genetic cause of sterile brain inflammation in a consanguineous Syrian family.
- To investigate the role of tripeptidyl peptidase II (TPP2) in neurological inflammation.
Main Methods:
- Homozygosity mapping and next-generation sequencing were used to identify the causative gene.
- RNA and protein expression studies, enzymatic assays, and immunohistochemistry were performed.
- Targeted sequencing of TPP2 in additional MS cases was conducted.
Main Results:
- A homozygous missense mutation (p.Cys28Gly) in the TPP2 gene was identified in affected siblings.
- Reduced TPP2 protein expression was observed in the affected siblings' blood.
- TPP2 protein was upregulated in the brain tissue of MS patients without TPP2 mutations.
Conclusions:
- The homozygous TPP2 mutation (p.Cys28Gly) is likely responsible for the observed inflammation phenotype.
- TPP2's role in MHC Class I epitope destruction suggests involvement in autoimmune processes.
- TPP2 may play a broader role in the inflammatory mechanisms of multiple sclerosis.
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