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

Abstract

Wolfram (DIDMOAD) syndrome is an autosomal recessive neurodegenerative disorder accompanied by insulin-dependent diabetes mellitus and progressive optic atrophy. Recent positional cloning led to identification of the WFS1 (Wolfram 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 studies indicated the WFS1 protein to be an integral, endoglycosidase H-sensitive membrane glycoprotein that localizes primarily in the endoplasmic reticulum (ER). Consistent with this, immunofluorescence cell staining of overexpressed WFS1 showed a characteristic reticular pattern over the cytoplasm and overlapped with the ER marker staining. No co-localization of WFS1 with mitochondria argues against an earlier clinical hypothesis that Wolfram syndrome is a mitochondria-mediated disorder. In the rat brain, at both the protein and mRNA level, WFS1 was found to be present predominantly in selected neurons in the hippocampus CA1, amygdaloid areas, olfactory tubercle and superficial layer of the allocortex. These expression sites, i.e. components of the limbic system or structures closely associated with this system, may be involved in the psychiatric, behavioral and emotional abnormalities characteristic of this syndrome. ER localization of WFS1 suggests that this protein plays an as yet undefined role in membrane trafficking, protein processing 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.

Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

“…Beta cells are selectively lost from the pancreatic islets and this loss is genetically programmed [10]. Our group and others previously identified the Wolfram syndrome gene, designating it WFS1 [11] or wolframin [12] and showing that it is localised primarily in the ER [13,14]. Homozygous Wfs1 knockout mice developed glucose intolerance.…”

Identification of homozygous WFS1 mutations (p.Asp211Asn, p.Gln486*) causing severe Wolfram syndrome and first report of male fertility

“…8,9 This gene is located on chromosome 4p16.3 and encodes Wolframin, a transmembrane protein that maintains calcium homeostasis of the endoplasmic reticulum (ER). [8][9][10][11] Other roles, such as regulation of ER stress and protein biosynthesis, modification/ folding, have also been suggested for Wolframin. [12][13][14][15] Wolframin is an 890 amino acid oligomeric protein with a molecular mass of 100 kDa.…”

Wolfram gene (WFS1) mutation causes autosomal dominant congenital nuclear cataract in humans

“…Previous studies have demonstrated that Wolframin is an endoplasmic reticulum (ER) membrane-embedded protein. 7 ER localization suggests that Wolframin has physiological function in membrane trafficking, secretion, processing and/or regulation of ER calcium homeostasis. Disturbances or overloading of these functions induce ER stress responses, including apoptosis.…”