Human Molecular Genetics Advance Access published online on July 1, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg214
© 2003 by Oxford University Press
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1 Institut für Diabetesforschung, Akademisches Lehrkrankenhaus Muenchen-Schwabing, Koelner Platz 1, 80804 Muenchen, Germany
* To whom correspondence should be addressed. E-mail: Sabine.Hofmann{at}lrz.uni-muenchen.de.
Mutations of the WFS1 gene are responsible for Wolfram syndrome, a rare, recessive disorder characterized by early-onset, non-autoimmune diabetes mellitus, optic atrophy and further neurological and endocrinological abnormalities. The WFS1 gene encodes wolframin, a putative multispanning membrane glycoprotein of the endoplasmic reticulum. The function of wolframin is completely unknown. In order to characterize wolframin, we have generated polyclonal antibodies against both hydrophilic termini of the protein. Wolframin was found to be ubiquitously expressed with highest levels in brain, pancreas, heart and insulinoma Here we investigate for the first time the molecular mechanisms that cause loss-of-function of wolframin in affected individuals. In patients harboring nonsense mutations complete absence of the mutated wolframin is caused by instability and rapid decay of WSF1 nonsense transcripts. In a patient carrying a compound heterozygous missense mutation, R629W, we found markedly reduced steady-state levels of wolframin. Pulse-chase experiments of mutant wolframin expressed in COS-7 cells indicated that the R629W mutation leads to instability and strongly reduced half-life of wolframin. Thus, Wolfram syndrome in patients investigated here is caused by reduced protein dosage rather than dysfunction of the mutant wolframin.
Article
Wolfram syndrome: structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product
2 Institut für Klinische Chemie, Molekulare Diagnostik und Mitochondriale Genetik, Akademisches Lehrkrankenhaus Muenchen-Schwabing, Koelner Platz 1, 80804 Muenchen, Germany
3 Institut für Klinische Chemie, Molekulare Diagnostik und Mitochondriale Genetik and Institut für Diabetesforschung, Akademisches Lehrkrankenhaus Muenchen-Schwabing, Koelner Platz 1, 80804 Muenchen, Germany
Abstract 
-cell lines. Analysis of the structural features provides experimental evidence that wolframin contains nine transmembrane segments and is embedded in the membrane in an Ncyt/Clum topology. Wolframin assembles into higher molecular weight complexes of about 400 kDa in the membrane. Pulse-chase experiments demonstrate that during maturation wolframin is N-glycosylated but lacks proteolytical processing. Moreover, N-glycosylation appears to be essential for the biogenesis and stability of wolframin.
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