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Human Molecular Genetics Advance Access originally published online on July 1, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 16 2003-2012
DOI: 10.1093/hmg/ddg214
© 2003 Oxford University Press

Wolfram syndrome: structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product

Sabine Hofmann1,*, Christine Philbrook1, Klaus-Dieter Gerbitz2 and Matthias F. Bauer1,2

1Institut für Diabetesforschung and 2Institut für Klinische Chemie, Molekulare Diagnostik und Mitochondriale Genetik, Akademisches Lehrkrankenhaus Muenchen-Schwabing, Koelner Platz 1, 80804 Muenchen, Germany

Received April 9, 2003; Accepted June 19, 2003

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 ß-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 ~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. 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 WFS1 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, the Wolfram syndrome in patients investigated here is caused by reduced protein dosage rather than dysfunction of the mutant wolframin.

* To whom correspondence should be addressed. Tel: +49 8930793134; Fax: +49 893081733; Email: sabine.hofmann{at}lrz.uni-muenchen.de


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