WFS1 Gene Research Articles

WS1 gene mutation analysis of Wolfram syndrome in a Chinese patient and a systematic review of literatures

Wolfram syndrome is a rare hereditary disease characterized by diabetes mellitus and optic atrophy. The outcome of this disease is always poor. WFS1 gene mutation is the main cause of this disease. A patient with diabetes mellitus, diabetes insipidus, renal tract disorder, psychiatric abnormality, and cataract was diagnosed with Wolfram syndrome. Mutations in open reading frame (ORF) of WFS1 gene was analyzed by sequencing. Mutations in WFS1 gene was also summarized by a systematic review in Pubmed and Chinese biological and medical database. Sequencing of WFS1 gene in this patient showed a new mutation, 1962G>A, and two other non-sense mutations, 2433A>G and 2565G>A. Systematic review included 219 patients in total and identified 172 WFS1 gene mutations, most of which were located in Exon 8. These mutations in WFS1 gene might be useful in prenatal diagnosis of Wolfram syndrome.

Primary diagnosis of Wolfram syndrome in an adult patient — Case report and description of a novel pathogenic mutation

Wolfram syndrome is a rare, autosomal recessive, neurodegenerative disorder presenting with the main clinical symptoms of childhood-onset diabetes mellitus, optic atrophy, diabetes insipidus and deafness (DIDMOAD). Later stages of the disease are dominated by neurological complications and death occurs early in life with a median life expectancy of 30 years. Here we present a 44 year old patient who presented to our hospital with central respiratory failure, cognitive impairment, ataxia and parkinsonism and was first diagnosed with Wolfram syndrome. DNA sequence analysis revealed a novel pathogenic mutation within the WFS1 gene. Advanced clinical and imaging studies performed in this patient highlight the neurodegenerative process in Wolfram syndrome and expand our knowledge on the mutational spectrum of the disease.

Wolfram syndrome and WFS1 gene

Wolfram syndrome (WS) (MIM 222300) is a rare multisystem neurodegenerative disorder of autosomal recessive inheritance, also known as DIDMOAD (diabetes insipidus, insulin-deficient diabetes mellitus, optic atrophy and deafness). A Wolfram gene (WFS1) has been mapped to chromosome 4p16.1 which encodes an endoplasmic reticulum (ER) membrane-embedded protein. ER localization suggests that WFS1 protein has physiological functions in membrane trafficking, secretion, processing and/or regulation of ER calcium omeostasis. Disturbances or overloading of these functions induce ER stress responses, including apoptosis. Most WS patients carry mutations in this gene, but some studies provided evidence for genetic heterogeneity, and the genotype-phenotype relationships are not clear. Here we review the data regarding the mechanisms and the mutations of WFS1 gene that relate to WS.

Implication of genetic variants near SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, FTO, TCF2, KCNQ1, and WFS1 in Type 2 Diabetes in a Chinese population

BackgroundRecently, several genome-wide and candidate gene association studies have identified many novel genetic loci for type 2 diabetes (T2D); among these genes, CDKAL1, IGF2BP2, SLC30A8, CDKN2A/B, HHEX, FTO, TCF2, KCNQ1, and WFS1 are the most important. We aimed to determine the effects of these genetic loci associated with T2D in the Chinese Han population of China.MethodsSingle-nucleotide polymorphisms (SNPs) in or near CDKAL1, IGF2BP2, SLC30A8, CDKN2A/B, HHEX, FTO, TCF2, KCNQ1, and WFS1 genes were genotyped in a case-control Chinese Han sample living in Beijing, China involving 1024 patients with T2D and 1005 control subjects.ResultsIn Chinese Han, we replicated the associations between 7 genetic loci and T2D, with risk allele-specific odds ratios (ORs) as follows: 1.27 (95% CI, 1.11-1.45; p = 0.0008) for CDKAL1-rs10946398, 1.26 (95% CI, 1.08-1.47; p = 0.003) for IGF2BP2-rs4402960, 1.19 (95% CI, 1.04-1.37; p = 0.009) for SLC30A8-rs13266634, 1.22 (95% CI, 1.06-1.41; p = 0.005) for CDKN2A/B-rs10811661, 1.20 (95% CI, 1.01-1.42; p = 0.03) for HHEX-rs5015480, 1.37 (95% CI, 1.19-1.69; p = 1.0 × 10-4) for KCNQ1-rs2237892, and 1.24 (95% CI, 1.01-1.52; p = 0.046) for FTO-rs8050136 after adjustment for age, gender, and body mass index. Not only did an association between WFS1-rs6446482 and early-onset T2D exist in the subgroup analysis, but TCF2-rs7501939 and WFS1-rs6446482 were also confirmed to confer risk for T2D in this meta-analysis. Moreover, the relationship between FTO-rs8050136 and body mass index, together with the effect of CDKAL1-rs10946398 on beta cell function, was also observed in the control individuals.ConclusionsOur findings support the important contribution of these genetic loci to susceptibility for T2D in the Chinese Han population in Beijing of China.

A Case of Wolfram Like Disorder with Type 2 Diabetes Mellitus in an Adult

Wolfram-like disorder is one of the WFS1-related disorders that are caused by mutation of the WFS1 genes. WFS1-related disorders are classified as Wolfram syndrome, Wolfram like disorder and nonsyndromic low-frequency sensorineural hearing loss (DFNA6/14/38). Wolfram syndrome is known to DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and deafness), and it is an autosomal-recessive disorder that predisposes a patient to developing type 1 diabetes in association with progressive optic atrophy, and the disease shows various phenotypes. Wolfram like disorder is an autosomal-dominant disorder that predisposes a patient to develop type 2 diabetes in association with optic atrophy and hearing impairment. We experienced a case of Wolfram like disorder with diabetes, optic atrophy and sensorineural hearing loss in a 28-year-old woman who was admitted to our hospital. Our case demonstrated the E737K missense mutation on the WFS1 gene, which has been previously reported in the medical literature. The diagnosis of WFS1-related disorder was confirmed by the clinical features and molecular genetic testing of the WFS1 gene.

A WFS1 Haplotype Consisting of the Minor Alleles of rs752854, rs10010131, and rs734312 Shows a Protective Role Against Type 2 Diabetes in Russian Patients

Rare variants of the WFS1 gene encoding wolframin cause Wolfram syndrome, a monogenic disease associated with diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. In contrast, common variants of WFS1 showed association with type 2 diabetes (T2D) in numerous Caucasian populations. In this study, we tested whether the markers rs752854, rs10010131, and rs734312, located in the WFS1 gene, are related to the development of T2D in a Russian population. The polymorphic markers were genotyped in Russian diabetic (n = 1,112) and non-diabetic (n = 1,097) patients using a Taqman allele discrimination assay. The correlation between the carriage of disease-associated WFS1 variants and the patients' clinical and metabolic characteristics was studied using ANOVA and ANCOVA. Adjustment for confounding variables such as gender, age, body mass index, obesity, HbA1c, and hypertension was made. Haplotype GAG, consisting of the minor alleles of rs752854, rs10010131, and rs734312, respectively, showed association with decreased risk of T2D (OR = 0.44, 95% CI = 0.32-0.61, p = 4.3 x 10(-7)). Compared to other WFS1 variants, non-diabetic individuals homozygous for GAG/CAG had significantly increased fasting insulin (p(adjusted) = 0.047) and homeostasis model assessment of β-cell function (HOMA-β) index (p(adjusted) = 0.006). Diabetic patients homozygous for GAG/GAG showed significantly elevated levels of 2-h insulin (p(adjusted) = 0.029) and HOMA-β = 0.011. Disease-associated variants of WFS1 contribute to the pathogenesis of T2D through impaired insulin response to glucose stimulation and altered β-cell function.

Pigmentary maculopathy in two siblings with wolfram syndrome.

To report pigmentary maculopathy in two siblings with Wolfram syndrome (WS), which is a rare neurodegenerative autosomal recessive disorder that predisposes the development of type 1 diabetes in association with progressive optic atrophy. We describe the ophthalmologic presentation of two white siblings with WS. Two brothers from a nonconsanguineous family had clinical characteristics of WS with type 1 diabetes and progressive optic atrophy at the age of 7 years to 8 years. Maculopathy pigmentary was discovered at the age of 20 years in the elder brother and at the age of 18 years in the younger brother. Diabetic retinopathy was absent. WFS1 gene investigation revealed two different inactivating mutations. A mitochondrial DNA mutation was not found in either patient. Further study is needed to determine the prevalence of this clinical presentation.

Additional heterozygous 2507A>C mutation of WFS1 in progressive hearing loss at lower frequencies

To describe the audiological profiles in a Japanese family with autosomal dominant hereditary sensorineural hearing loss (SNHL) and to identify the causative gene. A family study at an academic tertiary referral center. A family with autosomal dominant hereditary SNHL was enrolled. Hearing loss (HL) of affected members showed mid-frequency SNHL in childhood and progressed at lower frequencies with age, resulting in low-frequency SNHL. To understand the pathology of HL of this family, we performed a genetic analysis of WFS1, TECTA, and GJB2 by direct sequencing, and further audiovestibular examinations, including speech audiometry, distortion product otoacoustic emissions, electrocochleography, auditory brainstem responses, and electronystagmography for some affected members. A heterozygous A-to-C nucleotide transversion (c.2507A>C), resulting in a lysine-to-threonine substitution at codon 836 (K836T) was identified in exon 8 of WFS1. K836T was segregated with HL in the 15 participants in the genetic study but was not detected in the 212 normal chromosomes. Only polymorphic changes were detected in TECTA and GJB2. Audiovestibular examinations indicated purely cochlear HL and normal vestibular function. The summating potential/action potential ratios in electrocochleography increased in the bilateral ears of the proband. The family described with autosomal dominant inheritance of K836T of the WFS1 gene demonstrates a progressive hearing loss in the lower frequencies.

GJB2 Mutations in Patients with Nonsyndromic Hearing Loss from Croatia

The aim of the study was to determine (1) the frequency and type of mutations in the coding region of the GJB2 gene (sequencing), (2) the frequency of splice site mutation IVS1 + 1G > A in the GJB2 gene (multiplex ligation-dependent probe amplification analysis), (3) possible copy number changes in the GJB2, GJB3, GJB6, and WFS1 genes (multiplex ligation-dependent probe amplification analysis), and (4) the frequency of del(GJB6-D13S1830) in the GJB6 gene in 58 unrelated patients with nonsyndromic hearing loss from Croatia. About 44.8% of our patients presented with mutation in the GJB2 gene. We identified seven sequence variations. Six of them had previously been reported as disease related (35delG, W24X, V37I, L90P, 313del14, and IVS1 + 1G > A), and we report here for the first time one novel variant, -24A > C. We detected the greatest frequency of 35delG allele compared to the other alleles (35.3%). Allelic frequencies of other common mutations accounted for 2.6-0.9% of analyzed chromosomes. Neither GJB6 deletion nor copy number changes in the GJB2, GJB3, GJB6, and WFS1 genes were found. The 35delG/35delG genotype was associated with severe to profound hearing loss in 94% of 35delG homozygotes. High mutation rate (44%) indicates that testing of the GJB2 gene will clarify the genetic cause in almost half of the cases of recessive nonsyndromic hearing loss in Croatia.

Mutations in the WFS1 gene and low frequency hearing loss

Mutations in the WFS1 gene and low frequency hearing loss

Male mice with deleted Wolframin (Wfs1) gene have reduced fertility

BackgroundWolfram Syndrome (WS) is an autosomal recessive disorder characterised by non-autoimmune diabetes mellitus, optic atrophy, cranial diabetes insipidus and sensorineural deafness. Some reports have described hypogonadism in male WS patients. The aim of our study was to find out whether Wfs1 deficient (Wfs1KO) male mice have reduced fertility and, if so, to examine possible causes.MethodsWfs1KO mice were generated by homologous recombination. Both Wfs1KO and wild type (wt) male mice were mated with wt female mice. The number of litters and the number of pups were counted and pregnancy rates calculated. The motility and morphology of the sperm and the histology of testes were analysed. Serum testosterone and FSH concentrations were also measured.ResultsThe pregnancy rate in wt females mated with Wfs1KO males was significantly lower than in the control group (15% vs. 32%; p < 0.05), but there was no significant difference in litter size. Analysis of male fertility showed that, in the Wfs1KO group, eight males out of 13 had pups whereas in the control group all 13 males had at least one litter. Sperm motility was not affected in Wfs1KO mice, but Wfs1KO males had less proximal bent tails (14.4 +/- 1.2% vs. 21.5 +/- 1.3 p < 0.05) and less abnormal sperm heads (22.8 +/- 1.8 vs. 31.5 +/- 3.5, p < 0.05) than wt males. Testes histology revealed significantly reduced number of spermatogonia (23.9 +/- 4.9 vs. 38.1 +/- 2.8; p < 0.05) and Sertoli cells (6.4 +/- 0.5 vs. 9.2 +/- 1.0; p < 0.05) in Wfs1KO mice. Serum testosterone and FSH concentrations did not differ between the two groups.ConclusionThe impaired fertility of Wfs1KO male mice is most likely due to changes in sperm morphology and reduced number of spermatogenic cells. The exact mechanism through which the Wfs1 gene influences sperm morphology needs to be clarified in further studies.

Mitochondrial abnormalities drive cell death in Wolfram syndrome 2

Mitochondrial abnormalities drive cell death in Wolfram syndrome 2

Expression of the diabetes risk gene wolframin (WFS1) in the human retina

Wolfram syndrome 1 (WFS1, OMIM 222300), a rare genetic disorder characterized by optic nerve atrophy, deafness, diabetes insipidus and diabetes mellitus, is caused by mutations of WFS1, encoding WFS1/wolframin. Non-syndromic WFS1 variants are associated with the risk of diabetes mellitus due to altered function of wolframin in pancreatic islet cells, expanding the importance of wolframin. This study extends a previous report for the monkey retina, using immunohistochemistry to localize wolframin on cryostat and paraffin sections of human retina. In addition, the human retinal pigment epithelial (RPE) cell line termed ARPE-19 and retinas from both pigmented and albino mice were studied to assess wolframin localization. In the human retina, wolframin was expressed in retinal ganglion cells, optic axons and the proximal optic nerve. Wolframin expression in the human retinal pigment epithelium (RPE) was confirmed with intense cytoplasmic labeling in ARPE-19 cells. Strong labeling of the RPE was also found in the albino mouse retina. Cryostat sections of the mouse retina showed a more extended pattern of wolframin labeling, including the inner nuclear layer (INL) and photoreceptor inner segments, confirming the recent report of Kawano et al. [Kawano, J., Tanizawa, Y., Shinoda, K., 2008. Wolfram syndrome 1 (Wfs1) gene expression in the normal mouse visual system. J. Comp. Neurol. 510, 1–23]. Absence of these cells in the human specimens despite the use of human-specific antibodies to wolframin may be related to delayed fixation. Loss of wolframin function in RGCs and the unmyelinated portion of retinal axons could explain optic nerve atrophy in Wolfram Syndrome 1.

Relation between increased anxiety and reduced expression of alpha1 and alpha2 subunits of GABA A receptors in Wfs1-deficient mice

Mutations in the coding region of the WFS1 gene cause Wolfram syndrome, a rare multisystem neurodegenerative disorder of autosomal recessive inheritance. In clinical studies a relation between mutations in the Wfs1 gene and increased susceptibility for mood disorders has been established. According to our previous studies, mice lacking Wfs1 gene displayed increased anxiety in stressful environment. As the GABA-ergic system plays a significant role in the regulation of anxiety, we analyzed the expression of GABA-related genes in the forebrain structures of wild-type and Wfs1-deficient mice. Experimentally naïve Wfs1-deficient animals displayed a significant down-regulation of α1 (Gabra1) and α2 (Gabra2) subunits of GABA A receptors in the temporal lobe and frontal cortex. Exposure of wild-type mice to the elevated plus-maze decreased levels of Gabra1 and Gabra2 genes in the temporal lobe. A similar tendency was also established in the frontal cortex of wild-type animals exposed to behavioral test. In Wfs1-deficient mice the elevated plus-maze exposure did not induce further changes in the expression of Gabra1 and Gabra2 genes. By contrast, the expression of Gad1 and Gad2 genes, enzymes responsible for the synthesis of GABA, was not significantly affected by the exposure of mice to the elevated plus-maze or by the invalidation of Wfs1 gene. Altogether, the present study demonstrates that increased anxiety of Wfs1-deficient mice is probably linked to reduced expression of Gabra1 and Gabra2 genes in the frontal cortex and temporal lobe.

Relation of exploratory behaviour to plasma corticosterone and Wfs1 gene expression in Wistar rats

Male Wistar rats exhibit significant variations in exploratory behaviour in the elevated plus-maze (EPM) model of anxiety. We have now investigated the relation between exploratory behaviour and levels of corticosterone and systemic oxidative stress. Also, the expression levels of endocannabinoid-related and wolframin (Wfs1) genes were measured in the forebrain structures. The rats were divided into high, intermediate and low exploratory activity groups. Exposure to EPM significantly elevated the serum levels of corticosterone in all rats, but especially in the high exploratory group. Oxidative stress indices and expression of endocannabinoid-related genes were not significantly affected by exposure to EPM. Wfs1 mRNA level was highly dependent on exploratory behaviour of animals. In low exploratory activity rats, Wfs1 gene expression was reduced in the temporal lobe, whereas in high exploratory activity group it was reduced in the mesolimbic area and hippocampus. Altogether, present study indicates that in high exploratory activity rats, the activation of brain areas related to novelty seeking is apparent, whereas in low exploratory activity group the brain structures linked to anxiety are activated.

A common genetic variant in WFS1 determines impaired glucagon-like peptide-1-induced insulin secretion

WFS1 type 2 diabetes risk variants appear to be associated with impaired beta cell function, although it is unclear whether insulin secretion is affected directly or secondarily via alteration of insulin sensitivity. We aimed to investigate the effect of a common WFS1 single-nucleotide polymorphism on several aspects of insulin secretion. A total of 1,578 non-diabetic individuals (534 men and 1,044 women, aged 40 +/- 13 years, BMI 28.9 +/- 8.2 kg/m(2) [mean +/- SD]) at increased risk of type 2 diabetes were genotyped for rs10010131 within the WFS1 gene. All participants underwent an OGTT (and a subset additionally an IVGTT [n = 319]) and a hyperglycaemic clamp combined with glucagon-like peptide-1 (GLP-1) and arginine stimuli (n = 102). rs10010131 was associated with reduced OGTT-derived insulin secretion (p = 0.03). In contrast, insulin secretion induced by an i.v. glucose challenge in the IVGTT and hyperglycaemic clamp was not different between the genotypes. GLP-1 infusion combined with a hyperglycaemic clamp showed a significant reduction of the insulin secretion rate during the first and second phases of GLP-1-induced insulin secretion in carriers of the risk allele (reduction of 36% and 26%, respectively; p = 0.007 and p = 0.04, respectively). A common genetic variant in WFS1 specifically impairs GLP-1-induced insulin secretion independently of insulin sensitivity. This defect might explain the impaired insulin secretion in carriers of the risk allele and confer the increased risk of type 2 diabetes.

Wolfram syndrome 1 ( Wfs1) mRNA expression in the normal mouse brain during postnatal development

Wolfram syndrome is a rare genetic disorder accompanying diabetes insipidus, sensorineural hearing loss, neurological complications, and psychiatric illness. This syndrome has been attributed to mutations in the WFS1 gene. In this study, we made a detailed histochemical analysis of the distribution of Wfs1 mRNA in the brain of developing mice. There were three patterns of change in the strength of Wfs1 mRNA signals from birth to early adulthood. In type 1, the signals were weak or absent in neonates but strong or moderate in young adults. This pattern was observed in the CA1 field, parasubiculum, and entorhinal cortex. In type 2, the signals were of a relatively constant strength during development. This pattern was seen in limbic structures (e.g. subiculum and central amygdaloid nucleus) and brainstem nuclei (e.g. facial and chochlear nuclei). In type 3, the signals peaked in the second week of age. This pattern was observed in the thalamic reticular nucleus. Thus, Wfs1 mRNA was widely distributed in the normal mouse brain during postnatal development. This evidence may provide clues as to the physiological role of the Wfs1 gene in the central nervous system, and help to explain endocrinological, otological, neurological, and psychiatric symptoms in Wolfram syndrome patients.

Wfs1 gene deletion causes growth retardation in mice and interferes with the growth hormone pathway

The aim of present study was to describe changes in gene expression in the temporal lobe of mice induced by deletion of the Wfs1 gene. Temporal lobes samples were analyzed using Affymetrix Mouse Genome 420 2 GeneChips and expression profiles were functionally annotated with GSEA and Ingenuity Pathway Analysis. We found that Wfs1 mutant mice are significantly smaller (20.9 +/- 1.6 g) than their wild-type counterparts (31.0 +/- 0.6 g, P < 0.0001). This difference existed in 129S6 and C57B6 backgrounds. Interestingly, microarray analysis identified upregulation of growth hormone (GH) transcripts and functional analysis revealed activation of GH pathways. In line with microarray data, the level of IGF-1 in the plasma of Wfs1 mutant mice was significantly increased (P < 0.05). Thus, Wfs1 deletion induces growth retardation, whereas the GH pathway is activated. To test the interaction between the Wfs1 deletion and genomic background, mutant mice were backcrossed to two different genetic backgrounds. In line with previous studies, an interaction between a gene knockout and genetic background was found in gene expression profiles in the congenic region. However, genetic background did not alter the effect of the Wfs1 mutation on either body weight or GH pathway activation. Further studies are needed to describe biochemical and molecular changes of the growth hormone axis as well as in other hormones to clarify their role in growth retardation in the Wfs1 mutant mice.

Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

The WFS1 gene encodes an endoplasmic reticulum (ER) membrane-embedded protein called Wolfram syndrome 1 protein, homozygous mutations of which cause selective beta cell loss in humans. The function(s) of this protein and the mechanism by which the mutations of this gene cause beta cell death are still not fully understood. We hypothesised that increased insulin demand as a result of obesity/insulin resistance causes ER stress in pancreatic beta cells, thereby promoting beta cell death. We studied the effect of breeding Wfs1 ( -/- ) mice on a C57BL/6J background with mild obesity and insulin resistance, by introducing the agouti lethal yellow mutation (A ( y ) /a). We also treated the mice with pioglitazone. Wfs1 ( -/- ) mice bred on a C57BL/6J background rarely develop overt diabetes by 24 weeks of age, showing only mild beta cell loss. However, Wfs1 ( -/- ) A ( y ) /a mice developed selective beta cell loss and severe insulin-deficient diabetes as early as 8 weeks. This beta cell loss was due to apoptosis. In Wfs1 ( +/+ ) A ( y ) /a islets, levels of ER chaperone immunoglobulin-binding protein (BiP)/78 kDa glucose-regulated protein (GRP78) and phosphorylation of eukaryotic translation initiation factor 2, subunit alpha (eIF2alpha) apparently increased. Levels of both were further increased in Wfs1 ( -/- ) A ( y ) /a murine islets. Electron micrography revealed markedly dilated ERs in Wfs1 (-/-) A ( y ) /a murine beta cells. Interestingly, pioglitazone treatment protected beta cells from apoptosis and almost completely prevented diabetes development. Wfs1-deficient beta cells are susceptible to ER stress. Increased insulin demand prompts apoptosis in such cells in vivo. Pioglitazone, remarkably, suppresses this process and prevents diabetes. As common WFS1 gene variants have recently been shown to confer a risk of type 2 diabetes, our findings may be relevant to the gradual but progressive loss of beta cells in type 2 diabetes.

The novel compound heterozygous mutations, V434del and W666X, in WFS1 gene causing the Wolfram syndrome in a Chinese family

Wolfram syndrome (WFS), also known as DIDMOAD, is an infrequent cause of diabetes mellitus. WFS is an autosomal recessive neurodegenerative disease characterized by various clinical manifestations such as diabetes mellitus, optic atrophy, diabetes insipidus, deafness, neurological symptoms, renal tract abnormalities, psychiatric disorders, and gonadal disorders. The majority of patients with WFS carry the loss of function mutations in the WFS1 gene. The exons 2-8 of the WFS1 gene from one Chinese WFS patient were amplified by the polymerase chain reaction (PCR), subcloning techniques and direct sequence determination was applied to the amplified fragments. The compound heterozygous mutation of a 3-bp (GAC) deletion (V434del) and another compound heterozygous mutation (G-->N)(W666X) in exon 8 of WFS1 gene was identified in the patient. Other seventeen members of her family were investigated. Four cases with heterozygotes had been found through screening for the mutation V434del and five cases for the mutation W666X in the whole family. This is the first report of WFS with the mutation V434del and W666X in the WFS1 gene.