Abstract
Wolfram syndrome is an autosomal recessive neuro-degenerative disorder associated with juvenile onset non-autoimmune diabetes mellitus and progressive optic atrophy. The disease has been attributed to mutations in the WFS1 gene, which codes for a protein predicted to possess 9-10 transmembrane segments. Little is known concerning the function of the WFS1 protein (wolframin). Endoglycosidase H digestion, immunocytochemistry, and subcellular fractionation studies all indicated that wolframin is localized to the endoplasmic reticulum in rat brain hippocampus and rat pancreatic islet beta-cells, and after ectopic expression in Xenopus oocytes. Reconstitution of wolframin from oocyte membranes into planar lipid bilayers demonstrated that the protein induced a large cation-selective ion channel that was blocked by Mg2+ or Ca2+. Inositol triphosphate was capable of activating channels in the fused bilayers that were similar to channel components induced by wolframin expression. Expression of wolframin also increased cytosolic calcium levels in oocytes. Wolframin thus appears to be important in the regulation of intracellular Ca2+ homeostasis. Disruption of this function may place cells at risk to suffer inappropriate death decisions, thus accounting for the progressive beta-cell loss and neuronal degeneration associated with the disease.
Highlights
Wolfram syndrome, or diabetes insipidus, diabetes mellitus, optic atrophy disorder (DIDMOAD),1 is an autosomal recessive disease, suggesting a loss of function [1, 2]
Wolfram syndrome is an autosomal recessive neurodegenerative disorder associated with juvenile onset non-autoimmune diabetes mellitus and progressive optic atrophy
Wolfram syndrome is an autosomal recessive neurodegenerative disorder associated with juvenile onset non-autoimmune diabetes and progressive bilateral optic atrophy [1, 2]
Summary
Diabetes insipidus, diabetes mellitus, optic atrophy disorder (DIDMOAD), is an autosomal recessive disease, suggesting a loss of function [1, 2]. It was suggested that wolframin may be a mitochondrial protein [8], because many of the clinical features characteristic of this syndrome are similar to defects in oxidative phosphorylation that are seen in mitochondrial diseases, such as MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike symptoms), Leber’s hereditary optic neuropathy, and maternally inherited diabetes and deafness (mitochondrial diabetes). Supporting this hypothesis, deletions of mitochondrial DNA have been reported in some Wolfram patients [9]. Given that Ca2ϩ regulation by the ER is prominent in cellular apoptosis, these data suggest that wolframin may be involved in the regulation of ER-mediated cellular mortality and that a defect in this regulatory process is the cause of the progressive -cell loss and neuronal degeneration associated with the disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
