Mutation screening of the Wolfram syndrome gene in psychiatric patients

Torres, Rosarelis; Leroy, Elisabeth; Hu, Xun; Katrivanou, Aggeliki; Gourzis, Philippos; Papachatzopoulou, Adamantia; Athanassiadou, Aglaia; Beratis, Stavroula; Collier, David; Polymeropoulos, M H

doi:10.1038/sj.mp.4000787

Cited by 39 publications

(28 citation statements)

References 14 publications

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“…Also, in our patient series various polymorphisms, composed of silent variants or conservative amino acid changes, were detected, all of which have previously been reported (13)(14)(15)(16)(17).…”

Section: Mutations Of the Wfs1 Genementioning

confidence: 87%

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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Section: Mutations Of the Wfs1 Genementioning

confidence: 87%

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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“…The mutation H313Y in the TM1 domain (Figure 2a) has not been reported before, but other mutations in TM1 (M312R and A326V) have been reported in subjects with psychiatric disorder. 22,23 Figure 2b shows alignment of WFS1 from six different organisms, two primates, two rodents, one bird, and one fish. The overall conservation for WFS1 between the species is 99 -56%, and higher in the ER lumen C-terminal than in the cytoplasmatic N-terminal (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…22,24 Mutations in the WFS1 gene L Hansen et al unrelated family EE33. None of the parents carried this mutation ( Figure 1b) implicating a de novo mutation, and no other mutation was detected in the WFS1 coding regions.…”

Section: 1821mentioning

confidence: 99%

Mutation analysis of the WFS1 gene in seven Danish Wolfram syndrome families; four new mutations identified

et al. 2005

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Wolfram syndrome (WS) is a neuro-degenerative autosomal recessive (AR) disorder (OMIM #222300) caused by mutations in the WFS1 gene on 4p16.1. More than 120 mutations have been identified in WFS1 associated with AR WS, as well as autosomal dominant nonsyndromic low-frequency sensorineural hearing loss (LFSNHL). WFS1 variants were identified in eight subjects from seven families with WS, leading to the identification of four novel mutations, Q194X (nonsense), H313Y (missense), L313fsX360 (duplication frame shift) and F883fsX951 (deletion frame shift), and four previously reported mutations, A133T and L543R (missense), V415del (in frame triple deletion) and F883fsX950 (deletion frame shift). A mutation was found in 11/14 disease chromosomes, two subjects were homozygous for one mutation, one subject was compound heterozygous for two nucleotide substitutions (missense), one subject was compound heterozygous for a duplication and a deletion (frame shift), and in three families only one mutation was detected (Q194X and H313Y). All affected individuals shared clinically early-onset diabetes mellitus and progressive optic atrophy with onset in the first and second decades, respectively. In contrast, diabetes insipidus was present in two subjects only. Various degrees and types of hearing impairment were diagnosed in six individuals and cataract was observed in five subjects.

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“…They found no difference between groups in the frequency of the one common polymorphism that was the focus of their study. The A559T wolframin mutation was found in 2/147 patients in Torres et al, 13 1/204 in Crawford et al, 14 2/161 affective disorder patients in Serretti et al, 17 and 0/184 Japanese bipolar patients. 18 This mutation was present on the paternal side of one of the WS families in the present report.…”

Section: Discussionmentioning

confidence: 95%

“…Available population surveys [14][15][16][17][18] suggest that the population frequency of truncating mutations is less than 1%, and that the population frequency of missense mutations is greater than 1%. If the population frequency of wolframin mutations that predispose carriers to psychiatric illness is about 1%, with an odds ratio of 7.1, wolframin mutation carriers would be estimated to be about 7% of patients hospitalized for depression.…”

Section: Discussionmentioning

confidence: 99%

Wolframin mutations and hospitalization for psychiatric illness

Swift¹,

Swift

2005

Mol Psychiatry

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Genetic predisposition plays an important role in most common psychiatric disorders. The identification of a specific gene associated with a psychiatric illness can lead to improved management of the gene-associated disorder. Mutations in the wolframin gene are associated with mental illness. Many patients with the Wolfram syndrome (WS), who are homozygous or compound heterozygous for wolframin mutations, have severe psychiatric symptoms. In WS families, close blood relatives, who have a high probability of carrying a single wolframin mutation, had a statistically significant excess, over spouse controls, of psychiatric hospitalizations, attempted and completed suicides, and self-reports of mental illness. Since heterozygous carriers of wolframin mutations are relatively frequent in the population according to the general Hardy-Weinberg principle, such mutations might be responsible for the illnesses of many psychiatric patients. The hypothesis that heterozygous carriers of a wolframin mutation are predisposed to psychiatric illness was tested in subjects from 25 WS families. In all, 11 relatives who had psychiatric hospitalizations could be genotyped through mutation analysis. Eight of these carried the wolframin mutation transmitted in their family, significantly (one-sided P ¼ 0.0022) more than the 3.0 expected if there were no association between psychiatric hospitalizations and mutations at this locus. All eight mutation-positive subjects had been hospitalized for a major depression. This confirmation of the association is not influenced by confounders, undetected stratification, or genetic heterogeneity. The relative risk of psychiatric hospitalization for depression was estimated to be 7.1 (95% CI 1.9-26.6) for carriers of a single wolframin mutation compared to noncarriers. Molecular Psychiatry (2005) 10, 799-803.

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Mutation screening of the Wolfram syndrome gene in psychiatric patients

Cited by 39 publications

References 14 publications

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

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

Mutation analysis of the WFS1 gene in seven Danish Wolfram syndrome families; four new mutations identified

Wolframin mutations and hospitalization for psychiatric illness

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