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

Colosimo, Alessia; Guida, Valentina; Rigoli, Luciana; Bella, Chiara Di; Luca, Alessandro De; Briuglia, Silvana; Stuppia, Liborio; Salpietro, D. C.; Dallapiccola, Bruno

doi:10.1002/humu.10215

Cited by 51 publications

(53 citation statements)

References 22 publications

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“…Identified mutations consisting of insertions, deletions, nonsense, and missense were concentrated in the largest exon, exon 8, similar to other reports (1,2,7,15,18). Besides exon 8, we found a novel homozygous missense mutation in exon 5 in one patient.…”

Section: Discussionsupporting

confidence: 89%

“…Since the cloning of the WFS1 gene, genetic screening of WS patients has been performed mostly in Caucasian individuals (7,14,15,18). The Brazilian population is mostly of Portuguese origin, miscegenated with a variety of other populational groups including Italians, Spaniards, Japanese, Africans, and native Indians.…”

Section: Discussionmentioning

confidence: 99%

“…The non-coding exon 1 was sequenced only when no mutation was found in the coding region. Exons 1-7 were amplified using a set of primers as previously published (7). Exon 8, which was divided into seven regions, was amplified using primer pairs as described by Strom et al (2).…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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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 additional clinical conditions included diabetes insipidus (onset age of 9 years), deafness (7 years) and urinary tract dilation. 16 Table 1 compares the clinical features of this patient and patients from family 2. The c.1456C4T truncates the WFS1 protein after the fifth transmembrane segment resulting in a non-functional protein.…”

Section: Discussionmentioning

confidence: 99%

“…8,9 Although many mutations have been identified in the WFS1 gene, most affected patients carry a mutation, either insertion, deletion, nonsense or missense, in exon 8, the largest exon of WFS1. 8,9,[16][17][18][19] The C-terminal hydrophilic part of the protein is the major site for missense mutations. Studies indicate that mutations affecting the translation of the last 10-15 amino acids result in a severe disease phenotype that confirms the functional importance of the C-terminus.…”

Section: Introductionmentioning

confidence: 99%

Identification of homozygous WFS1 mutations (p.Asp211Asn, p.Gln486*) causing severe Wolfram syndrome and first report of male fertility

Haghighi

Setoodeh

et al. 2012

Eur J Hum Genet

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Wolfram syndrome (WFS) is a neurodegenerative genetic condition characterized by juvenile-onset of diabetes mellitus and optic atrophy. We studied clinical features and the molecular basis of severe WFS (neurodegenerative complications) in two consanguineous families from Iran. A clinical and molecular genetic investigation was performed in the affected and healthy members of two families. The clinical diagnosis of WFS was confirmed by the existence of diabetes mellitus and optic atrophy in the affected patients, who in addition had severe neurodegenerative complications. Sequencing of WFS1 was undertaken in one affected member from each family. Targeted mutations were tested in all members of relevant families. Patients had most of the reported features of WFS. Two affected males in the first family had fathered unaffected children. We identified two homozygous mutations previously reported with apparently milder phenotypes: family 1: c.631G4A (p.Asp211Asn) in exon 5, and family 2: c.1456C4T (p.Gln486*) in exon 8. Heterozygous carriers were unaffected. This is the first report of male Wolfram patients who have successfully fathered children. Surprisingly, they also had almost all the complications associated with WFS. Our report has implications for genetic counseling and family planning advice for other affected families.

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Identification of novel mutations in WFS1 and genotype–phenotype correlation in Wolfram syndrome

Cano

Rouzier

Monnot

et al. 2007

American J of Med Genetics Pt A

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Mutations in the WFS1 gene have been reported in Wolfram syndrome (WS), an autosomal recessive disorder defined by early onset of diabetes mellitus (DM) and progressive optic atrophy. Because of the low prevalence of this syndrome and the recent identification of the WFS1 gene, few data are available concerning the relationships between clinical and molecular aspects of the disease. Here, we describe 12 patients from 11 families with WS. We report on eight novel (A214fsX285, L293fsX303, P346L, I427S, V503fsX517, R558C, S605fsX711, P838L) and seven previously reported mutations. We also looked for genotype-phenotype correlation both in patients included in this study and 19 additional WS patients that were previously reported. Subsequently, we performed a systematic review and meta-analysis of five published clinical and molecular studies of WFS1 for genotype-phenotype correlation, combined with our current French patient group for a total of 96 patients. The presence of two inactivating mutations was shown to predispose to an earlier age of onset of both DM and optic atrophy. Moreover, the clinical expression of WS was more complete and occurred earlier in patients harboring no missense mutation.

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

Cited by 51 publications

References 22 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

Identification of homozygous WFS1 mutations (p.Asp211Asn, p.Gln486*) causing severe Wolfram syndrome and first report of male fertility

Identification of novel mutations in WFS1 and genotype–phenotype correlation in Wolfram syndrome

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