Wolfram Syndrome in the Japanese Population; Molecular Analysis of <i>WFS1</i> Gene and Characterization of Clinical Features

<div><p>Background</p><p>Wolfram syndrome (WFS) is a recessive neurologic and endocrinologic degenerative disorder, and is also known as DIDMOAD (<u>D</u>iabetes <u>I</u>nsipidus, early-onset <u>D</u>iabetes <u>M</u>ellitus, progressive <u>O</u>ptic <u>A</u>trophy and <u>D</u>eafness) syndrome. Most affected individuals carry recessive mutations in the Wolfram syndrome 1 gene (<i>WFS1</i>). However, the phenotypic pleiomorphism, rarity and molecular complexity of this disease complicate our efforts to understand WFS. To address this limitation, we aimed to describe complications and to elucidate the contributions of <i>WFS1</i> mutations to clinical manifestations in Japanese patients with WFS.</p><p>Methodology</p><p>The minimal ascertainment criterion for diagnosing WFS was having both early onset diabetes mellitus and bilateral optic atrophy. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106906#s3" target="_blank">Genetic analysis</a> for <i>WFS1</i> was performed by direct sequencing.</p><p>Principal Findings</p><p>Sixty-seven patients were identified nationally for a prevalence of one per 710,000, with 33 patients (49%) having all 4 components of DIDMOAD. In 40 subjects who agreed to participate in this investigation from 30 unrelated families, the earliest manifestation was DM at a median age of 8.7 years, followed by OA at a median age of 15.8 years. However, either OA or DI was the first diagnosed feature in 6 subjects. In 10, features other than DM predated OA. Twenty-seven patients (67.5%) had a broad spectrum of recessive mutations in <i>WFS1</i>. Two patients had mutations in only one allele. Eleven patients (27.5%) had intact <i>WFS1</i> alleles. Ages at onset of both DM and OA in patients with recessive <i>WFS1</i> mutations were indistinguishable from those in patients without <i>WFS1</i> mutations. In the patients with predicted complete loss-of-function mutations, ages at the onsets of both DM and OA were significantly earlier than those in patients with predicted partial-loss-of function mutations.</p><p>Conclusion/Significance</p><p>This study emphasizes the clinical and genetic heterogeneity in patients with WFS. Genotype-phenotype correlations may exist in patients with <i>WFS1</i> mutations, as demonstrated by the disease onset.</p></div

Comparison of ages at onset of diabetes mellitus and optic atrophy in subjects with and without a mutated <i>WFS1</i> gene.

<p>*Data are expressed as means±SD.</p><p>Comparison of ages at onset of diabetes mellitus and optic atrophy in subjects with and without a mutated <i>WFS1</i> gene.</p

<i>WFS1</i> mutations in each patient with WFS.

<p>*Novel mutations are indicated in boldface.</p>§<p>Individual with detectable <i>WFS1</i> mutation in single chromosome.</p><p><i>WFS1</i> mutations in each patient with WFS.</p

Analysis of genotype-phenotype correlations for <i>WFS1</i> mutations.

<p>Ages at onset of both diabetes mellitus (A) and optic atrophy (B) in each patient in the three groups are shown graphically with the mean age indicated on the vertical axis. Patients are color-coated according to the mutation categories: group 1 (n = 15) in red, group 2 (n = 9) in blue and group 3 (n = 3) in green. The differences between group 1 and group 2 were statistically significant: diabetes mellitus 4.4±1.9 years vs. 13.4±9.9 years, <i>p</i> = 0.008, and optic atrophy 9.6±6.9 years vs. 22.5±12.4 years, <i>p</i> = 0.014, respectively. Data are expressed as means ± SD.</p

A schematic presentation of mutations affecting the WFS1 protein.

<p>The relative positions of WFS1 mutations within the putative WFS1 protein topology are indicated. Mutations are color-coded according to their mutation categories: mutations with predicted complete loss of function (red), mutations with predicted partial loss of function (blue). Novel mutations are indicated in bold type.</p

Prevalence of complications in 67 patients with WFS.

<p>Prevalence of complications in 67 patients with WFS.</p

Clinical characteristics and family history of each patient screened for <i>WFS1</i> mutations.

<p>*M, male; F, female; DM, diabetes mellitus; OA, optic atrophy; D, deafness; DI, diabetes insipidus, numbers indicate age at onset in years; +, symptomatic with unknown onset age; −, asymptomatic, Y; Yes, N; No, N/A; not applicable, □; consanguineous marriage and affected siblings.</p>§<p>Individual with detectable <i>WFS1</i> mutation in single chromosome.</p><p>Clinical characteristics and family history of each patient screened for <i>WFS1</i> mutations.</p