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Molecular characterization of WFS1 in patients with Wolfram syndrome.

ABSTRACT: 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.

SUBMITTER: van ven Ouweland JM

PROVIDER: S-EPMC1907324 | biostudies-literature | 2003 May

REPOSITORIES: biostudies-literature

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Molecular characterization of WFS1 in patients with Wolfram syndrome.

van ven Ouweland Johannes M W JM Cryns Kim K Pennings Ronald J E RJ Walraven Inge I Janssen George M C GM Maassen J Antonie JA Veldhuijzen Bernard F E BF Arntzenius Alexander B AB Lindhout Dick D Cremers Cor W R J CW Van Camp Guy G Dikkeschei Lambert D LD

The Journal of molecular diagnostics : JMD 20030501 2

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 fa ...[more]

PMID: 12707373

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Project description:BackgroundWolfram syndrome (WFS) is a recessive neurologic and endocrinologic degenerative disorder, and is also known as DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus, progressive Optic Atrophy and Deafness) syndrome. Most affected individuals carry recessive mutations in the Wolfram syndrome 1 gene (WFS1). However, the phenotypic pleiomorphism, rarity and molecular complexity of this disease complicate our efforts to understand WFS. To address this limitation, we aimed to describe complications and to elucidate the contributions of WFS1 mutations to clinical manifestations in Japanese patients with WFS.MethodologyThe minimal ascertainment criterion for diagnosing WFS was having both early onset diabetes mellitus and bilateral optic atrophy. Genetic analysis for WFS1 was performed by direct sequencing.Principal findingsSixty-seven patients were identified nationally for a prevalence of one per 710,000, with 33 patients (49%) having all 4 components of DIDMOAD. In 40 subjects who agreed to participate in this investigation from 30 unrelated families, the earliest manifestation was DM at a median age of 8.7 years, followed by OA at a median age of 15.8 years. However, either OA or DI was the first diagnosed feature in 6 subjects. In 10, features other than DM predated OA. Twenty-seven patients (67.5%) had a broad spectrum of recessive mutations in WFS1. Two patients had mutations in only one allele. Eleven patients (27.5%) had intact WFS1 alleles. Ages at onset of both DM and OA in patients with recessive WFS1 mutations were indistinguishable from those in patients without WFS1 mutations. In the patients with predicted complete loss-of-function mutations, ages at the onsets of both DM and OA were significantly earlier than those in patients with predicted partial-loss-of function mutations.Conclusion/significanceThis study emphasizes the clinical and genetic heterogeneity in patients with WFS. Genotype-phenotype correlations may exist in patients with WFS1 mutations, as demonstrated by the disease onset.

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Molecular characterization of WFS1 in patients with Wolfram syndrome.

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Molecular characterization of WFS1 in patients with Wolfram syndrome.

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