[Positional cloning of the gene(WFS1) for Wolfram syndrome]

Wolfram syndrome(DIDMOAD syndrome) is an autosomal recessive neurodegenerative disorder characterized by juvenile-onset, insulin-requiring diabetes mellitus and optic atrophy. Other symptoms including diabetes insipidus, neurosensory deafness, urinary tract and neurological abnormalities are often accompanied. In patients, beta-cells are selectively lost from their pancreatic islets of Langerhans. The gene was previously mapped to 4p16.1. By haplotype analysis and recombination mapping in 5 families, we localized the gene within a region less than 250 kb on chromosome 6p. In the region, we identified a novel gene(WFS1) encoding a putative transmembrane protein. Mutations were identified in all affected members of the families and these mutations were associated with disease phenotype. This finding was further confirmed by other investigators and to date, more than 50 mutations were identified in the WFS1 gene from the patients with Wolfram syndrome. The WFS1 gene encodes a protein of 100.3 kDa with 9 to 10 putative transmembrane domains. The protein appears to be important in the survival and maintenance of normal pancreatic beta-cells and neurons. Physiological function of the WFS1 protein and mechanisms by which defective WFS1 lead to the development of Wolfram syndrome need to be clarified.