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  • 1.
    Reinthaler, Eva M.
    et al.
    Med Univ Vienna, Dept Neurol, Vienna, Austria.
    Graf, Elisabeth
    Helmholtz Zentrum Munchen, Inst Humangenet, Munich, Germany.
    Zrzavy, Tobias
    Med Univ Vienna, Ctr Brain Res, Vienna, Austria.
    Wieland, Thomas
    Helmholtz Zentrum Munchen, Inst Humangenet, Munich, Germany.
    Hotzy, Christoph
    Kopecky, Chantal
    Med Univ Vienna, Dept Internal Med 3, Div Nephrol & Dialysis, Vienna, Austria.
    Pferschy, Sandra
    Med Univ Vienna, Dept Neurol, Vienna, Austria.
    Schmied, Christiane
    Med Univ Vienna, Dept Neurol, Vienna, Austria.
    Leutmezer, Fritz
    Med Univ Vienna, Dept Neurol, Vienna, Austria.
    Keilani, Mohammad
    Med Univ Vienna, Rehabil & Occupat Med, Dept Phys Med, Vienna, Austria.
    Lill, Christina M.
    Univ Lubeck, Inst Neurogenet & Cardiogenet, Lubeck Interdisciplinary Platform Genome Analyt, Lubeck, Germany;Johannes Gutenberg Univ Mainz, Univ Med Ctr, Focus Program Translat Neurosci FTN, Dept Neurol, Mainz, Germany;Johannes Gutenberg Univ Mainz, Univ Med Ctr, Neuroimaging Ctr NIC, Mainz, Germany.
    Hoffjan, Sabine
    Ruhr Univ Bochum, Dept Human Genet, Bochum, Germany.
    Epplen, Joerg T.
    Ruhr Univ Bochum, Dept Human Genet, Bochum, Germany;Univ Witten, Fac Hlth, ZBAF, Herdecke, Witten, Germany.
    Zettl, Uwe K.
    Univ Rostock, Neuroimmunol Sect, Dept Neurol, Rostock, Germany.
    Hecker, Michael
    Univ Rostock, Neuroimmunol Sect, Dept Neurol, Rostock, Germany.
    Deutschlaender, Angela
    Jeweils Mayo Clin, Dept Neurol, Jacksonville, FL USA;Jeweils Mayo Clin, Dept Clin Genom, Jacksonville, FL USA;Jeweils Mayo Clin, Dept Neurosci, Jacksonville, FL USA.
    Meuth, Sven G.
    Univ Munster, Dept Neurol, Munster, Germany.
    Ahram, Mamoun
    Univ Jordan, Sch Med, Dept Physiol & Biochem, Amman, Jordan.
    Mustafa, Baha
    Univ Jordan, Sch Med, Dept Physiol & Biochem, Amman, Jordan.
    El-Khateeb, Mohammed
    Natl Ctr Inst Diabet, Endocrinol & Genet NCDEG, Amman, Jordan.
    Vilarino-Guell, Cartes
    Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada.
    Sadovnick, Dessa
    Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada.
    Zimprich, Fritz
    Med Univ Vienna, Dept Neurol, Vienna, Austria.
    Tomkinson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Strom, Tim
    Helmholtz Zentrum Munchen, Inst Humangenet, Munich, Germany.
    Kristoferitsch, Wolfgang
    SMZ Ost Donauspital, Karl Landsteiner Inst Neuroimmunol & Neurodegener, Vienna, Austria;SMZ Ost Donauspital, Inst Neuroimmunol & Neurodegenerat Disorders, Vienna, Austria.
    Lassmann, Hans
    Med Univ Vienna, Ctr Brain Res, Vienna, Austria.
    Zimprich, Alexander
    Med Univ Vienna, Dept Neurol, Vienna, Austria.
    TPP2 mutation associated with sterile brain inflammation mimicking MS2018In: NEUROLOGY-GENETICS, ISSN 2376-7839, Vol. 4, no 6, article id UNSP e285Article in journal (Refereed)
    Abstract [en]

    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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