2. Academic Validation
  3. TPP2 mutation associated with sterile brain inflammation mimicking MS

TPP2 mutation associated with sterile brain inflammation mimicking MS

  • Neurol Genet. 2018 Nov 13;4(6):e285. doi: 10.1212/NXG.0000000000000285.
Eva M Reinthaler 1,  Elisabeth Graf 1,  Tobias Zrzavy 1,  Thomas Wieland 1,  Christoph Hotzy 1,  Chantal Kopecky 1,  Sandra Pferschy 1,  Christiane Schmied 1,  Fritz Leutmezer 1,  Mohammad Keilani 1,  Christina M Lill 1,  Sabine Hoffjan 1,  Jörg T Epplen 1,  Uwe K Zettl 1,  Michael Hecker 1,  Angela Deutschländer 1,  Sven G Meuth 1,  Mamoun Ahram 1,  Baha Mustafa 1,  Mohammed El-Khateeb 1,  Carles Vilariño-Güell 1,  A Dessa Sadovnick 1,  Fritz Zimprich 1,  Birgitta Tomkinson 1,  Tim Strom 1,  Wolfgang Kristoferitsch 1,  Hans Lassmann 1,  Alexander Zimprich 1
Affiliations

Affiliation

  • 1 Department 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.
PMID: 30533531 DOI: 10.1212/NXG.0000000000000285
Abstract

Objective: To ascertain the genetic cause of a consanguineous family from Syria suffering from a sterile brain inflammation mimicking a mild nonprogressive form of MS.

Methods: We used homozygosity mapping and next-generation Sequencing to detect the disease-causing gene in the affected siblings. In addition, we performed RNA and protein expression studies, enzymatic activity assays, immunohistochemistry, and targeted Sequencing of further MS cases from Austria, Germany, Canada and Jordan.

Results: In this study, we describe the identification of a homozygous missense mutation (c.82T>G, p.Cys28Gly) in the tripeptidyl peptidase II (TPP2) gene in all 3 affected siblings of the family. Sequencing of all TPP2-coding exons in 826 MS cases identified one further homozygous missense variant (c.2027C>T, p.Thr676Ile) in a Jordanian MS patient. TPP2 protein expression in whole blood was reduced in the affected siblings. In contrast, TPP2 protein expression in postmortem brain tissue from MS patients without TPP2 mutations was highly upregulated.

Conclusions: The homozygous TPP2 mutation (p.Cys28Gly) is likely responsible for the inflammation phenotype in this family. TPP2 is an ubiquitously expressed serine peptidase that removes tripeptides from the N-terminal end of longer Peptides. TPP2 is involved in various biological processes including the destruction of major histocompatibility complex Class I epitopes. Recessive loss-of-function mutations in TPP2 were described in patients with Evans syndrome, a rare autoimmune disease affecting the hematopoietic system. Based on the gene expression results in our MS autopsy brain samples, we further suggest that TPP2 may play a broader role in the inflammatory process in MS.

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