Disease relevance of WFS1

• Wolfram syndrome is an autosomal recessive neurodegenerative disorder characterized by juvenile-onset diabetes mellitus and progressive optic atrophy. mtDNA deletions have been described, and a gene (WFS1) recently has been identified, on chromosome 4p16, encoding a predicted 890 amino acid transmembrane protein [1].
• Dominantly inherited progressive hearing loss DFNA38 is caused by heterozygosity for a novel mutation in WFS1, the gene for recessively inherited Wolfram syndrome [2].
• WFS1 mutations in Spanish patients with diabetes mellitus and deafness [3].
• Recently, a novel gene for a putative transmembrane protein (WFS1/wolframin) was found to be mutated in patients with Wolfram syndrome or DI-DM-OA-D (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome [4].
• A gene responsible for Wolfram Syndrome (WFS1) has been recently identified on chromosome 4p16 [5].

Psychiatry related information on WFS1

• WFS1 gene mutation search in depressive patients: detection of five missense polymorphisms but no association with depression or bipolar affective disorder [6].
• Wolfram syndrome and suicide: Evidence for a role of WFS1 in suicidal and impulsive behavior [7].
• These results did not support the pathophysiological significance of WFS1 in bipolar disorder [8].

High impact information on WFS1

• Wolfram syndrome (WFS; OMIM 222300) is an autosomal recessive neurodegenerative disorder defined by young-onset non-immune insulin-dependent diabetes mellitus and progressive optic atrophy [9].
• Mutations in a novel gene (WFS1) encoding a putative transmembrane protein were found in all affected individuals in six WFS families, and these mutations were associated with the disease phenotype [9].
• On the basis of meiotic recombinants and disease-associated haplotypes, the WFS gene was localized to a BAC/P1 contig of less than 250 kb [9].
• Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome [10].
• Wolfram syndrome is the association of diabetes mellitus and optic atrophy, and is sometimes called DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) [10].

Chemical compound and disease context of WFS1

• The WFS1 gene, encoding an endoplasmic reticulum (ER) membrane glycoprotein, is mutated in Wolfram syndrome characterized by diabetes mellitus and optic atrophy [11].
• We identified one novel WFS1 missense mutation E864K, c.2590G-->A in exon 8 that co-segregates with ADOA combined with hearing impairment and impaired glucose regulation [12].
• Vasopressin secretion in the DIDMOAD (Wolfram) syndrome [13].

Biological context of WFS1

• We identified 24 mutations in the WFS1 gene: 8 nonsense mutations, 8 missense mutations, 3 in-frame deletions, 1 in-frame insertion, and 4 frameshift mutations [1].
• Clinical and molecular genetic analysis of 19 Wolfram syndrome kindreds demonstrating a wide spectrum of mutations in WFS1 [1].
• Herein we report five different heterozygous missense mutations (T699M, A716T, V779M, L829P, G831D) in the WFS1 gene found in six LFSNHL families [14].
• Other rare variants of WFS1 co-inherited with deafness in the family could be excluded as disease-causing mutations on the basis of this hearing-associated haplotype [2].
• WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells [15].

Anatomical context of WFS1

• The WFS1 gene encodes wolframin, a putative multispanning membrane glycoprotein of the endoplasmic reticulum [16].
• These results indicate that the pathogenesis of Wolfram syndrome involves chronic ER stress in pancreatic beta-cells caused by the loss of function of WFS1 [15].
• In this study, we generated a specific antibody against the C-terminus of the WFS1 protein and investigated its subcellular localization in cultured cells [17].
• 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 [17].
• No co-localization of WFS1 with mitochondria argues against an earlier clinical hypothesis that Wolfram syndrome is a mitochondria-mediated disorder [17].

Associations of WFS1 with chemical compounds

• Direct DNA sequencing was done to screen the entire coding region of the WFS1 gene in 30 patients from 19 British kindreds with Wolfram syndrome [1].
• Treatment of fibroblasts and MIN6 cells with thapsigargin or tunicamycin increased WFS1 mRNA [18].
• Inositol triphosphate was capable of activating channels in the fused bilayers that were similar to channel components induced by wolframin expression [19].
• A response to 'Rapidly repeated intravenous boluses of salbutamol for acute severe asthma' Sellers WFS, Messahel B, Anaesthesia 2003; 58: 680-3 [20].

Regulatory relationships of WFS1

• XBP1 induces WFS1 through an endoplasmic reticulum stress response element-like motif in SH-SY5Y cells [21].

Other interactions of WFS1

• Recently, pathogenetic mutations have been identified in two genetic diseases frequently co-morbid with mood disorder; WFS1 for Wolfram syndrome and ATP2A2 (SERCA2) for Darier's disease [22].
• Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss [14].
• Current potential candidates for screening include SLC26A4, in the presence of specific temporal bone anomalies, and WFS1, in the presence of a low-frequency hearing loss [23].
• Bleeding diathesis is a new additional feature to the clinical spectrum of WS, which is probably a feature of the disorder WFS2 and not WFS1, as bleeding has never been reported in the latter [24].
• The CRMP1 and EVC genes are located near WFS1, the Wolfram syndrome type 1 gene, in which mutations also cause low frequency sensorineural hearing loss (LFSNHL) [25].

Analytical, diagnostic and therapeutic context of WFS1

• METHODS: We searched for mutations in exon 8 of WFS1 in 30 depressive patients with a history of hospitalization and whose age at onset was under 40 years [6].
• Consistent with this, immunofluorescence cell staining of overexpressed WFS1 showed a characteristic reticular pattern over the cytoplasm and overlapped with the ER marker staining [17].
• Here we present sequence analysis of the WFS1 coding sequence in five affected individuals from two chromosome 4p-linked families [26].
• Here we report prenatal diagnosis by analysing the WFS1 gene, in a foetus belonging to a family with a child diagnosed for Wolfram syndrome [27].
• 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 [19].

References