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TPP2 mutation associated with sterile brain inflammation mimicking MS
Med Univ Vienna, Dept Neurol, Vienna, Austria.
Helmholtz Zentrum Munchen, Inst Humangenet, Munich, Germany.
Med Univ Vienna, Ctr Brain Res, Vienna, Austria.ORCID iD: 0000-0001-8909-1591
Helmholtz Zentrum Munchen, Inst Humangenet, Munich, Germany.
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2018 (English)In: NEUROLOGY-GENETICS, ISSN 2376-7839, Vol. 4, no 6, article id UNSP e285Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
2018. Vol. 4, no 6, article id UNSP e285
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-376411DOI: 10.1212/NXG.0000000000000285ISI: 000455099800009PubMedID: 30533531OAI: oai:DiVA.org:uu-376411DiVA, id: diva2:1287385
Available from: 2019-02-11 Created: 2019-02-11 Last updated: 2019-02-11Bibliographically approved

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Zrzavy, TobiasHecker, MichaelTomkinson, Birgitta
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