WFS1 mutations in Spanish patients with diabetes mellitus and deafness

Domènech, Enric; Gómez-Zaera, Montse; Nunes, Virginia

doi:10.1038/sj.ejhg.5200823

Cited by 35 publications

(26 citation statements)

References 14 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].…”

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confidence: 78%

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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: 78%

“…6.5% (95% CI [0. 8,12.1] increase per allele, p=0.025). Similar results were observed for 30 min serum insulin and Cpeptide after an oral glucose load (ESM Table 2).…”

Section: Resultsmentioning

confidence: 95%

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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“…77 An additional locus for WS has been identi¢ed at Ch.4q22-24, suggesting the syndrome is genetically heterogeneous. 78 …”

Section: Hypothalamic Diabetes Insipidusmentioning

confidence: 99%

Vasopressin and disorders of water balance: the physiology and pathophysiology of vasopressin

Ball

2007

Ann Clin Biochem

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Disorders of water balance are a common feature of clinical practice. An understanding of the physiology and pathophysiology of the key endocrine regulator of water balance vasopressin (VP) is key to diagnosis and management of these disorders. Diabetes insipidus is the result of a lack of VP or (less commonly) resistance to the renal effects of the hormone. Diagnostic testing can clarify aetiology and direct appropriate management. VP production can be associated with hyponatraemia. A comprehensive assessment of cardiovascular status and pharmacological influences are needed in these circumstances to differentiate between primary (inappropriate) and secondary (appropriate) physiological VP production. As with diabetes insipidus, diagnostic testing can help define the aetiology of hyponatraemia and direct appropriate management. Patients with disorders of water balance benefit from a joint clinical and laboratory medicine approach to diagnosis and management.

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“…It has been postulated to be a transmembrane endoglycosidase protein, mainly localized in the endoplasmic reticulum and involved in membrane trafficking, protein processing, and/or in the anti-apoptotic machinery for the survival of islet beta-cells [Gerbitz, 1999]. So far, more than 60 different causative molecular defects and 30 neutral polymorphisms in the WFS1 gene have been reported, most of which are private mutations [Domenech et al, 2002;Gomez-Zaera et al, 2001;Khanim et al, 2001;Tessa et al, 2001]. Among the inactivating changes, the most prevalent are frameshift alterations (40% of total) and missense changes (35%), followed by nonsense mutations (21%).…”

Section: Introductionmentioning

confidence: 99%

Molecular detection of novel WFS1 mutations in patients with Wolfram syndrome by a DHPLC-based assay

et al. 2003

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Communicated by Paolo FortinaWolfram syndrome (WS) is a recessively inherited mendelian form of diabetes and neurodegeneration also known by the acronym DIDMOAD from the major clinical features, including diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Affected individuals may also show renal tract abnormalities as well as multiple neurological and psychiatric symptoms. The causative gene for WS (WFS1) encoding wolframin maps to chromosome 4p16.1 and consists of eight exons, spanning 33.44 Kb of genomic DNA. In this study we report on the mutational analysis of the WFS1 coding region in 19 Italian WS patients and 25 relatives, using a DHPLC-based protocol. A total of 19 different mutations in WFS1 were found in 18 of 19 patients (95%). All these mutations, except one, are novel, preferentially located in WFS1 exon 8, and include deletions, insertions, duplications, and nonsense and missense changes. In particular, a 16 base-pair deletion in WFS1 codon 454 was detected in five different unrelated nuclear families, being the most prevalent alteration in this Italian group. Nine neutral changes and polymorphisms were also identified. Overall, this study represents the molecular characterization of the largest cohort of Italian WS patients and carriers studied so far, and increases the number of identified WFS1 allelic variants worldwide. Hum Mutat 21:622-629,

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WFS1 mutations in Spanish patients with diabetes mellitus and deafness

Cited by 35 publications

References 14 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

Vasopressin and disorders of water balance: the physiology and pathophysiology of vasopressin

Molecular detection of novel WFS1 mutations in patients with Wolfram syndrome by a DHPLC-based assay

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