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Wolfram syndrome‐associated mutations lead to instability and proteasomal degradation of wolframin
Author(s) -
Hofmann Sabine,
Bauer Matthias F.
Publication year - 2006
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2006.06.036
Subject(s) - degradation (telecommunications) , lead (geology) , instability , mutation , genome instability , chemistry , genetics , biology , biochemistry , dna , dna damage , computer science , gene , physics , telecommunications , paleontology , mechanics
Wolfram syndrome is caused by mutations in WFS1 encoding wolframin, a polytopic membrane protein of the endoplasmic reticulum. Here, we investigated the molecular pathomechanisms of four missense and two truncating mutations in WFS1 . Expression in COS‐7 cells as well as direct analysis of patient cells revealed that WFS1 mutations lead to drastically reduced steady‐state levels of wolframin. All mutations resulted in highly unstable proteins which were delivered to proteasomal degradation. No wolframin aggregates were found in patient cells suggesting that Wolfram syndrome is not a disease of protein aggregation. Rather, WFS1 mutations cause loss‐of‐function by cellular depletion of wolframin.