WFS1 (Wolfram syndrome 1) gene product: predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain

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.