WFS1 (Wolfram syndrome 1) gene product: predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain
K. Takeda et al., WFS1 (Wolfram syndrome 1) gene product: predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain, HUM MOL GEN, 10(5), 2001, pp. 477-484
Wolfram (DIDMOAD) syndrome is an autosomal recessive neurodegenerative diso
rder accompanied by insulin-dependent diabetes mellitus and progressive opt
ic atrophy. Recent positional cloning led to identification of the WFS1 (Wo
lfram syndrome 1) gene, a member of a novel gene family of unknown function
. In this study, we generated a specific antibody against the C-terminus of
the WFS1 protein and investigated its subcellular localization in cultured
cells. We also studied its distribution in the rat brain. Biochemical stud
ies indicated the WFS1 protein to be an integral, endoglycosidase H-sensiti
ve membrane glycoprotein that localizes primarily in the endoplasmic reticu
lum (ER). Consistent with this, immunofluorescence cell staining of overexp
ressed WFS1 showed a characteristic reticular pattern over the cytoplasm an
d overlapped with the ER marker staining, No co-focalization of WFS1 with m
itochondria argues against an earlier clinical hypothesis that Wolfram synd
rome is a mitochondria-mediated disorder. In the rat brain, at both the pro
tein and mRNA level, WFS1 was found to be present predominantly in selected
neurons in the hippocampus CA1, amygdaloid areas, olfactory tubercle and s
uperficial layer of the allocortex. These expression sites, i.e. components
of the limbic system or structures closely associated with this system, ma
y be involved in the psychiatric, behavioral and emotional abnormalities ch
aracteristic of this syndrome. ER localization of WFS1 suggests that this p
rotein plays an as yet undefined role in membrane trafficking, protein proc
essing and/or regulation of ER calcium homeostasis. These studies represent
a first step toward the characterization of WFS1 protein, which presumably
functions to maintain certain populations of neuronal and endocrine cells.