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Abstract of Research conducted by Washington University, St.Louis, Missouri, USA
General description
Wolfram syndrome is a genetic disorder that is frequently seen in affected individuals as juvenile onset diabetes mellitus and optic atrophy, along with diabetes insipidus and deafness. Most patients with this progressive, neurodegenerative disorder eventually develop all four symptoms and die prematurely. The form of diabetes seen in these patients is ‘insulin-dependent non-autoimmune diabetes mellitus’ and occurs at 6 years as the mean age of onset. When the pancreas from these individuals were examined, the islet cells were dying, and insulin producing (beta)-cells were selectively absent. This syndrome is inherited as autosomal recessive, implying that both the copies of the gene in any individual need to be defective to show the symptoms associated with this disease. It has also been noted that carriers of this syndrome, i.e. those who have only one defective copy of the gene, are estimated to represent 1% of the US population and are predisposed to psychiatric illness. While studying Wolfram’s patients from at least 3 different ethnic backgrounds, our laboratory has used linkage mapping and other genetic techniques to link a region of chromosome 4 to this syndrome. Further, we have isolated a gene from this region and found it to be defective in all Wolfram patients in our study. We have named this gene, Wfs-1.
Based on the observation that insulin producing (beta)-cells are absent in the affected individuals and on the initial molecular characterization of the Wfs-1 gene, we propose that the gene plays an important role in the survival of the (beta)-cells. To this end, we hope to first study the role of the gene in the development of diabetes in mice. Our strategy is to mutate the gene in mice and study the resulting phenotype. More specifically we are interested to see why a defect in the Wfs-1 gene renders the insulin producing cells, incapable of survival and thus assign a role for this gene in normal animals. We hope to apply this knowledge to the study of diabetes in humans. This gene can possibly be the target for new drugs developed to counter auto-immune diabetes mellitus, where progressive death of ?-cells is the primary cause of the disease. Further, the gene itself might represent a therapeutic agent for blocking the onset of diabetes by means of modern gene therapy procedures.
Scientific Abstract
Wolfram syndrome (WFS) was first described in 1938 as a combination of familial juvenile-onset diabetes mellitus and optic atrophy. Most patients with this progressive disorder die prematurely with widespread atrophic changes throughout the brain. Insulin-requiring diabetes mellitus occurs with mean age of onset at 6 years. When examined, pancreatic islets were atrophic and insulin-producing (beta)-cells selectively absent. The disease is believed to account for 1/150 patients with young-onset insulin-requiring diabetes mellitus. The pathogenesis of Wolfram syndrome is unknown. Linkage of the gene to markers on chromosome 4p was reported in 1994 and recently we were successful in the positional cloning of the WFS gene (WFS1). Comparison of the cDNA sequence of WFS1 with those in public databases revealed no related genes. This novel cDNA sequence codes for a polypeptide of 890 amino acid residues. Hydrophobicity analysis predicts the gene product to be a membrane protein.