Wolfram Syndrome: New Mutations, Different Phenotype

Abstract

BackgroundWolfram Syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness identified by the acronym “DIDMOAD”. The WS gene, WFS1, encodes a transmembrane protein called Wolframin, which recent evidence suggests may serve as a novel endoplasmic reticulum calcium channel in pancreatic β-cells and neurons. WS is a rare disease, with an estimated prevalence of 1/550.000 children, with a carrier frequency of 1/354.The aim of our study was to determine the genotype of WS patients in order to establish a genotype/phenotype correlation.Methodology/Principal FindingsWe clinically evaluated 9 young patients from 9 unrelated families (6 males, 3 females). Basic criteria for WS clinical diagnosis were coexistence of insulin-treated diabetes mellitus and optic atrophy occurring before 15 years of age. Genetic analysis for WFS1 was performed by direct sequencing.Molecular sequencing revealed 5 heterozygous compound and 3 homozygous mutations. All of them were located in exon 8, except one in exon 4. In one proband only an heterozygous mutation (A684V) was found. Two new variants c.2663 C>A and c.1381 A>C were detected.Conclusions/SignificanceOur study increases the spectrum of WFS1 mutations with two novel variants. The male patient carrying the compound mutation [c.1060_1062delTTC]+[c.2663 C>A] showed the most severe phenotype: diabetes mellitus, optic atrophy (visual acuity 5/10), deafness with deep auditory bilaterally 8000 Hz, diabetes insipidus associated to reduced volume of posterior pituitary and pons. He died in bed at the age of 13 years. The other patient carrying the compound mutation [c.409_424dup16]+[c.1381 A>C] showed a less severe phenotype (DM, OA).

Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype

“…36 We analyzed as mutations (i) c.2020G→A (p.Gly674Arg), considered either a mutation 37 or a polymorphism, 38 and (ii) c.1367G→A (p.Arg456His), considered either a mutation 34 or a polymorphism, [31][32][33]39,40 because both are predicted to produce deleterious proteins by Condel 41 and PolyPhen-2. 42 c.2020G→A is also considered a mutation in the LOVD-WFS1 database.…”

“…We considered as polymorphisms c.*47C→T 33,43,44 and c.*253G→A 37 because they locate to the 3′-untranslated region of WFS1 mRNA, and c.316-37C→T because its effects on splicing have not been indicated. 34 Supplementary Table S2 online lists all the mutations described in the patients.…”

Association of Wolfram syndrome with Fallot tetralogy in a girl

“…Aloi et al, reported a Wolfram syndrome patient with surgically repaired tetralogy of Fallot due to a compound heterozygous mutation, c.1628T>G and c.2104G>A. 7 In the series by Strom et al, the patient harboring the mutation, as our patient, (c.1523delAT) exhibited a severe phenotype with an early onset of cardinal clinical manifestations including abnormal EEG and retarded sexual maturation. In the reported case, the finding of a WFS1 mutation in exon 8 was not associated with a cardiac anomaly.…”

“…Wolframin has a role in maintaining the homeostasis of endoplasmic reticulum in pancreatic β cells. 3 Cardiac malformations in Wolfram syndrome have been reported rarely [4][5][6][7] and may be responsible for the morbidity and mortality of the disorder. We present a case with Wolfram syndrome accompanied by tetralogy of Fallot and discuss the findings with reference to literature.…”

Asociación entre el síndrome de Wolfram y la tetralogía de Fallot en una niña

“…Aloi y col., informaron sobre un paciente con síndrome de Wolfram con tetralogía de Fallot sometida a reparación quirúrgica debido a una mutación heterocigota compuesta, c.1628T>G y c.2104G>A. 7 En una serie de Strom y col., el paciente que tenía la mutación (c.1523delAT), como nuestra paciente, tenía un fenotipo grave con la aparición temprana de manifestaciones clínicas primordiales, entre otras, anomalías en el EEG y retraso de la madurez sexual. En el caso notificado, el hallazgo de una mutación en el exón 8 del gen WFS1 no estaba asociado con anomalía cardíaca.…”