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