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

Abstract

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.

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

“…To date, seven causative mutations have been identified within exon 5, of which five mutations [17][18][19]25,26 result in WFS, whereas two mutations 27,28 are associated with low-frequency sensorineural hearing loss. p.Asp211Asn is located in the N-terminal domain of the WFS1 protein.…”

“…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.…”

Stress hypERactivation in the β-cell

“…54 This disease has been characterized as having four cardinal components: diabetes insipidus, diabetes mellitus, optic atrophy and deafness, of which only diabetes mellitus and optical atrophy are required to make a diagnosis. [55][56][57][58] Diabetes mellitus typically becomes symptomatic in the first decade of life, with a mean age of 6, while optic atrophy follows in the second decade (mean age of 12) 59,60 (Fig. 3).…”

“…There is also preliminary evidence that WFS1 regulates a key transcription factor of the UPR, ATF6, through the ubiquitin-proteasome pathway. Higher expression of WFS1 in b-cells, prevents hyperactivation of ER stress signaling with urinary tract abnormalities and neuropsychiatric impairment, 61 while powdered cataract and retinopathy can also be seen in a fraction of these patients 60,61 (Fig. 3).…”

Heterozygous Deletion of Exon 8 in WFS1 Gene in Two Wolfram Syndrome Probands with Hearing Loss: Case Report

“…Gas pa rin et al 13 re por ted no vel mu ta ti ons in exon 8 of WFS1 ge ne in 27 Bra zi li an pa ti ents with WFS. Ho mozy go us and/or com po und he te rozy gous WFS1 mu ta ti ons we re re por ted in WFS in Leba non po pu la ti on.…”