Autosomal dominant optic atrophy associated with hearing impairment and impaired glucose regulation caused by a missense mutation in the WFS1 gene

Eiberg, Hans; Hansen, Lars Hestbjerg; Kjer, Birgit; Hansen, Torben; Pedersen, Oluf; Bille, Mikkel; Rosenberg, Thomas; Tranebjærg, Lisbeth

doi:10.1136/jmg.2005.034892

Cited by 127 publications

(105 citation statements)

References 31 publications

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“…In this animal model, beta cell death occurred by an accelerated process of apoptosis; similarly, increased levels of markers reflecting ER stress were also demonstrated [7][8][9]. In line with the outcome of studies in mice, previous and statistically undersized human studies have indicated that variation in WFS1 may be associated with type 1 diabetes mellitus [10], type 2 diabetes mellitus [11] and a combination of diabetes mellitus and deafness [12,13]. Moreover, two patients with the Wolfram syndrome were reported to be without insulin-producing beta cells [14].…”

supporting

confidence: 77%

Impact of polymorphisms in WFS1 on prediabetic phenotypes in a population-based sample of middle-aged people with normal and abnormal glucose regulation

et al. 2008

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Aim/hypothesis Recently, variants in WFS1 have been shown to be associated with type 2 diabetes. We aimed to examine metabolic risk phenotypes of WFS1 variants in glucosetolerant people and in individuals with abnormal glucose regulation. Methods The type 2 diabetes-associated WFS1 variant rs734312 (His611Arg) was studied in the population-based Inter99 cohort involving 4,568 glucose-tolerant individuals and 1,471 individuals with treatment-naive abnormal glucose regulation, and in an additional 3,733 treated type 2 diabetes patients. ResultsThe WFS1 rs734312 showed a borderline significant association with type 2 diabetes with directions and relative risks consistent with previous reports. In individuals with abnormal glucose regulation, the diabetogenic risk A allele of rs734312 was associated in an allele-dependent manner with a decrease in insulinogenic index (p=0.025) and decreased 30-min serum insulin levels (p=0.047) after an oral glucose load. In glucose-tolerant individuals the same allele was associated with increased fasting serum insulin concentration (p=0.019) and homeostasis model assessment of insulin resistance (HOMA-IR; p=0.026). To study the complex interaction of WFS1 rs734312 on insulin release Diabetologia (2008) and insulin resistance we introduced Hotelling's T 2 test. Assuming bivariate normal distribution, we constructed standard error ellipses of the insulinogenic index and HOMA-IR when stratified according to glucose tolerance status around the means of each WFS1 rs734312 genotype level. The interaction term between individuals with normal glucose tolerance and abnormal glucose regulation on the insulinogenic index and HOMA-IR was significantly associated with the traits (p=0.0017). Conclusions/interpretation Type 2 diabetes-associated risk alleles of WFS1 are associated with estimates of a decreased pancreatic beta cell function among middle-aged individuals with abnormal glucose regulation.

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confidence: 77%

Impact of polymorphisms in WFS1 on prediabetic phenotypes in a population-based sample of middle-aged people with normal and abnormal glucose regulation

et al. 2008

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“…Giuliano et al noted an atypical phenotype in a patient whose WFS1 coding region had only one mutation identified (14). In addition, a rare form of autosomal dominant transmission of diabetes mellitus, deafness, optic atrophy, and no other manifestations of Wolfram disease was associated with the E864K mutation in two families (28,29). Thus, the location of WFS1 mutations also seems important to determine the severity of disease.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel mutations of the WFS1 gene in Brazilian patients with Wolfram syndrome

Gasparin

Crispim

Paula

et al. 2009

European Journal of Endocrinology

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Objective: Wolfram syndrome (WS) is a rare, progressive, neurodegenerative disorder with an autosomal recessive pattern of inheritance. The gene for WS, WFS1, was identified on chromosome 4p16 and most WS patients carry mutations in this gene. However, some studies have provided evidence for genetic heterogeneity and the genotype-phenotype relationships are not clear. Our aim was to ascertain the spectrum of WFS1 mutations in Brazilian patients with WS and to examine the phenotype-genotype relationships in these patients. Design and methods: Clinical characterization and analyses of the WFS1 gene were performed in 27 Brazilian patients with WS from 19 families. Results: We identified 15 different mutations in the WFS1 gene in 26 patients, among which nine are novel. All mutations occurred in exon 8, except for one missense mutation which was located in exon 5. Although we did not find any clear phenotype-genotype relationship in patients with mutations in exon 8, the homozygous missense mutation in exon 5 was associated with a mild phenotype: onset of diabetes mellitus and optic atrophy during adulthood with good metabolic control being achieved with low doses of sulfonylurea. Conclusions: Our data show that WFS1 is the major gene involved in WS in Brazilian patients and most mutations are concentrated in exon 8. Also, our study increases the spectrum of WFS1 mutations. Although no clear phenotype-genotype relationship was found for mutations in exon 8, a mild phenotype was associated with a homozygous missense mutation in exon 5.

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“…A missense mutation (E864K) in the WFS1 gene was also reported in a Danish family with autosomal-dominant juvenile-onset optic atrophy in combination with hearing impairment. 16 Rendtorff et al 17 reported a pair of siblings, followed over 17 years, who manifested congenital or early childhood cataracts, diabetes insipidus, diabetes mellitus, optic atrophy and deafness. Recently WFS was described in a 44-year-old patient with diabetes mellitus, central respiratory failure, cognitive impairment, ataxia and parkinsonism.…”

Section: Discussionmentioning

confidence: 99%

Wolfram gene (WFS1) mutation causes autosomal dominant congenital nuclear cataract in humans

et al. 2013

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Autosomal dominant optic atrophy associated with hearing impairment and impaired glucose regulation caused by a missense mutation in the WFS1 gene

Cited by 127 publications

References 31 publications

Impact of polymorphisms in WFS1 on prediabetic phenotypes in a population-based sample of middle-aged people with normal and abnormal glucose regulation

Impact of polymorphisms in WFS1 on prediabetic phenotypes in a population-based sample of middle-aged people with normal and abnormal glucose regulation

Identification of novel mutations of the WFS1 gene in Brazilian patients with Wolfram syndrome

Wolfram gene (WFS1) mutation causes autosomal dominant congenital nuclear cataract in humans

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