title: 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.
  
  
  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.
authors.affiliation: Division of Endocrinology, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Maria Regina R
authors.initials: MR
authors.lastname: Gasparin
authors.forename: Felipe
authors.initials: F
authors.lastname: Crispim
authors.forename: Sílvia L
authors.initials: SL
authors.lastname: Paula
authors.forename: Maria Beatriz S
authors.initials: MB
authors.lastname: Freire
authors.forename: Ivaldir S
authors.initials: IS
authors.lastname: Dalbosco
authors.forename: Thais Della
authors.initials: TD
authors.lastname: Manna
authors.forename: João Eduardo N
authors.initials: JE
authors.lastname: Salles
authors.forename: Fábio
authors.initials: F
authors.lastname: Gasparin
authors.forename: Aléxis
authors.initials: A
authors.lastname: Guedes
authors.forename: João M
authors.initials: JM
authors.lastname: Marcantonio
authors.forename: Márcio
authors.initials: M
authors.lastname: Gambini
authors.forename: Camila P
authors.initials: CP
authors.lastname: Salim
authors.forename: Regina S
authors.initials: RS
authors.lastname: Moisés
mesh_terms: D000293:Adolescent; D000328:Adult; D001938:Brazil; D002648:Child; D005091:Exons / Q000235:genetics; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D014929:Wolfram Syndrome / Q000235:genetics*; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; C114987:wolframin protein