RT Journal Article SR Electronic T1 TPP2 mutation associated with sterile brain inflammation mimicking MS JF Neurology Genetics JO Neurol Genet FD Lippincott Williams & Wilkins SP e285 DO 10.1212/NXG.0000000000000285 VO 4 IS 6 A1 Reinthaler, Eva M. A1 Graf, Elisabeth A1 Zrzavy, Tobias A1 Wieland, Thomas A1 Hotzy, Christoph A1 Kopecky, Chantal A1 Pferschy, Sandra A1 Schmied, Christiane A1 Leutmezer, Fritz A1 Keilani, Mohammad A1 Lill, Christina M. A1 Hoffjan, Sabine A1 Epplen, Jörg T. A1 Zettl, Uwe K. A1 Hecker, Michael A1 Deutschländer, Angela A1 Meuth, Sven G. A1 Ahram, Mamoun A1 Mustafa, Baha A1 El-Khateeb, Mohammed A1 Vilariño-Güell, Carles A1 Sadovnick, A. Dessa A1 Zimprich, Fritz A1 Tomkinson, Birgitta A1 Strom, Tim A1 Kristoferitsch, Wolfgang A1 Lassmann, Hans A1 Zimprich, Alexander YR 2018 UL http://ng.neurology.org/content/4/6/e285.abstract AB 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.ERCC5=excision repair cross-complementation group 5; ExAC=exome aggregation consoritum; LoF=loss of function; MAF=minor allele frequency; MHC=major histocompatibility complex; NAWM=normal-appearing white matter; PBMC=peripheral blood mononuclear cell; TPP2=tripeptidyl peptidase II; TRIANGLE=TPP2-related immunodeficiency, autoimmunity and neurodevelopmental delay with impaired glycolysis and lysosomal expansion