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JMD 2003, Vol. 5, No. 2
Copyright © 2003 American Society for Investigative Pathology & Association for Molecular Pathology

Molecular Characterization of WFS1 in Patients with Wolfram Syndrome

Johannes M. W. Van Den Ouweland^*, Kim Cryns, Ronald J. E. Pennings, Inge Walraven^*, George M. C. Janssen, J. Antonie Maassen, Bernard F. E. Veldhuijzen^¶, Alexander B. Arntzenius^||, Dick Lindhout^**, Cor W. R. J. Cremers, Guy Van Camp and Lambert D. Dikkeschei^*

From the Department of Clinical Chemistry * Isala Klinieken, Weezenlanden, Zwolle, The Netherlands; the Department of Medical Genetics, University of Antwerp, Antwerp, Belgium; the Department of Otorhinolaryngology, UMC St. Radboud, Nijmegen, The Netherlands; the Department of Molecular Cell Biology, Leiden University Medical Centre, Leiden, The Netherlands; the Department of Internal Diseases, ^¶ Amphia Hospital, Breda; The Netherlands; the Department of Internal Diseases, ^|| Spaarne Hospital, Haarlem, The Netherlands; and the Department of Medical Genetics, ** University Medical Center Utrecht, Utrecht, The Netherlands

Wolfram (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome is a rare autosomal-recessive neurodegenerative disorder that is characterized by juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing impairment. A gene responsible for Wolfram syndrome (WFS1) has been identified on the short arm of chromosome 4 and subsequently mutations in WFS1 have been described. We have screened 12 patients with Wolfram syndrome from nine Dutch families for mutations in the WFS1-coding region by single-strand conformation polymorphism analysis and direct sequencing. Furthermore, we analyzed the mitochondrial genome for gross abnormalities and the A3243G point mutation in the leucyl-tRNA gene, because Wolfram syndrome shows phenotypic similarities with mitochondrial disease. Seven mutations in WFS1 were identified in six of nine families: two missense mutations, one frameshift mutation, one splice donor site mutation, and three deletions. In addition, a splice variant near the 5'UTR of WFS1 was identified, present in patient as well as control RNA samples in various percentages, alternating the translation initiation consensus sequence. Whether this WFS1 splice variant displays impaired translation efficiency remains to be determined. No MtDNA lesions were identified in any of the Wolfram patients. Our results demonstrate the usefulness of molecular analysis of WFS1 in the refinement of clinical diagnostic criteria for Wolfram syndrome that helps to dissect the clinically overlapping syndromes sharing diabetes mellitus and optic atrophy.