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      Wolfram Syndrome: New Mutations, Different Phenotype


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          Wolfram Syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness identified by the acronym “DIDMOAD”. The WS gene, WFS1, encodes a transmembrane protein called Wolframin, which recent evidence suggests may serve as a novel endoplasmic reticulum calcium channel in pancreatic β-cells and neurons. WS is a rare disease, with an estimated prevalence of 1/550.000 children, with a carrier frequency of 1/354.

          The aim of our study was to determine the genotype of WS patients in order to establish a genotype/phenotype correlation.

          Methodology/Principal Findings

          We clinically evaluated 9 young patients from 9 unrelated families (6 males, 3 females). Basic criteria for WS clinical diagnosis were coexistence of insulin-treated diabetes mellitus and optic atrophy occurring before 15 years of age. Genetic analysis for WFS1 was performed by direct sequencing.

          Molecular sequencing revealed 5 heterozygous compound and 3 homozygous mutations. All of them were located in exon 8, except one in exon 4. In one proband only an heterozygous mutation (A684V) was found. Two new variants c.2663 C>A and c.1381 A>C were detected.


          Our study increases the spectrum of WFS1 mutations with two novel variants. The male patient carrying the compound mutation [c.1060_1062delTTC]+[c.2663 C>A] showed the most severe phenotype: diabetes mellitus, optic atrophy (visual acuity 5/10), deafness with deep auditory bilaterally 8000 Hz, diabetes insipidus associated to reduced volume of posterior pituitary and pons. He died in bed at the age of 13 years. The other patient carrying the compound mutation [c.409_424dup16]+[c.1381 A>C] showed a less severe phenotype (DM, OA).

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          A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome).

          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. Linkage to markers on chromosome 4p was confirmed in five families. 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. 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. WFS1 appears to function in survival of islet beta-cells and neurons.
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            Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells.

            Wolfram syndrome is an autosomal-recessive disorder characterized by insulin-dependent diabetes mellitus, caused by nonautoimmune loss of beta cells, and neurological dysfunctions. We have previously shown that mutations in the Wolfram syndrome 1 (WFS1) gene cause Wolfram syndrome and that WFS1 has a protective function against ER stress. However, it remained to be determined how WFS1 mitigates ER stress. Here we have shown in rodent and human cell lines that WFS1 negatively regulates a key transcription factor involved in ER stress signaling, activating transcription factor 6alpha (ATF6alpha), through the ubiquitin-proteasome pathway. WFS1 suppressed expression of ATF6alpha target genes and repressed ATF6alpha-mediated activation of the ER stress response element (ERSE) promoter. Moreover, WFS1 stabilized the E3 ubiquitin ligase HRD1, brought ATF6alpha to the proteasome, and enhanced its ubiquitination and proteasome-mediated degradation, leading to suppression of ER stress signaling. Consistent with these data, beta cells from WFS1-deficient mice and lymphocytes from patients with Wolfram syndrome exhibited dysregulated ER stress signaling through upregulation of ATF6alpha and downregulation of HRD1. These results reveal a role for WFS1 in the negative regulation of ER stress signaling and in the pathogenesis of diseases involving chronic, unresolvable ER stress, such as pancreatic beta cell death in diabetes.
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              Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein.

              Wolfram syndrome is an autosomal recessive disorder characterized by juvenile diabetes mellitus, diabetes insipidus, optic atrophy and a number of neurological symptoms including deafness, ataxia and peripheral neuropathy. Mitochondrial DNA deletions have been described in a few patients and a locus has been mapped to 4p16 by linkage analysis. Susceptibility to psychiatric illness is reported to be high in affected individuals and increased in heterozygous carriers in Wolfram syndrome families. We screened four candidate genes in a refined critical linkage interval covered by an unfinished genomic sequence of 600 kb. One of these genes, subsequently named wolframin, codes for a predicted transmembrane protein which was expressed in various tissues, including brain and pancreas, and carried loss-of-function mutations in both alleles in Wolfram syndrome patients.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                4 January 2012
                : 7
                : 1
                [1 ]Pediatric Clinic, University of Genoa, IRCCS G. Gaslini Institute, Genoa, Italy
                [2 ]Centro de Investigacion Biomedica en Red (CIBER) de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Barcelona, Spain
                [3 ]Division of Nephrology, Department of Medicine, Columbia University, New York, New York, United States of America
                [4 ]Laboratory on Pathophysiology of Uremia and Department of Nephrology, IRCCS G. Gaslini Institute, Genoa, Italy
                RIKEN Brain Science Institution, Japan
                Author notes

                Conceived and designed the experiments: CA AS LP RL GDA. Performed the experiments: CA AS LP. Analyzed the data: CA AS FL. Contributed reagents/materials/analysis tools: CA AS KP CR RT GMG. Wrote the paper: CA AS RL GDA.

                Aloi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 6
                Research Article
                Anatomy and Physiology
                Endocrine System
                Computational Biology
                Population Genetics
                Evolutionary Biology
                Evolutionary Processes
                Population Genetics
                Genetic Mutation
                Human Genetics
                Population Genetics
                Molecular Cell Biology
                Anatomy and Physiology
                Endocrine System
                Clinical Genetics
                Clinical Immunology
                Autoimmune Diseases
                Clinical Research Design
                Diagnostic Medicine
                Diabetic Endocrinology



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