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TPP2 mutation associated with sterile brain inflammation mimicking MS.
Neurol. Genet. 4:e285 (2018)
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 () gene in all 3 affected siblings of the family. Sequencing of all -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 mutations was highly upregulated. Conclusions: The homozygous mutation (p.Cys28Gly) is likely responsible for the inflammation phenotype in this family. 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 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 may play a broader role in the inflammatory process in MS.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
e-ISSN 2376-7839
Zeitschrift Neurology Genetics
Quellenangaben Band: 4, Heft: 6, Seiten: , Artikelnummer: e285 Supplement: ,
Verlagsort Minneapolis, Minn.
Begutachtungsstatus peer-reviewed