.. _WFS1: WFS1 ^^^^ .. contents:: :local: General Information ******************* :Full gene name: Wolfram syndrome 1 (wolframin) :Entrez Gene ID: 7466 :Location: 4p16.1 :Synonyms: WFS, WFSL, WFRS :Type: protein-coding User SNPs ********* SNPs given by the user that are near or inside this gene: +------------+---------------+-----------+ | SNP | Distance (bp) | Direction | +============+===============+===========+ | rs10010131 | 0 | within | +------------+---------------+-----------+ .. _WFS1 Gene summary: NCBI Summary ************ This gene encodes a transmembrane protein, which is located primarily in the endoplasmic reticulum and ubiquitously expressed with highest levels in brain, pancreas, heart, and insulinoma beta-cell lines. Mutations in this gene are associated with Wolfram syndrome, also called DIDMOAD (\ ``Diabetes``\ Insipidus, \ ``Diabetes``\ Mellitus, Optic Atrophy, and Deafness), an autosomal recessive disorder. The disease affects the brain and central nervous system. Mutations in this gene can also cause autosomal dominant deafness 6 (DFNA6), also known as DFNA14 or DFNA38. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2009] .. _OMIM ID 606201 : http://omim.org/entry/606201 .. _WFS1 OMIM Text: OMIM **** :OMIM ID: `OMIM ID 606201 `_ **Allelic Variants (Selected Examples)** .0001 WOLFRAM SYNDROME 1 In 3 affected sibs with Wolfram syndrome (222300) in a consanguineous Japanese family, Inoue et al. (1998) found a TC deletion at position 2812 in the WFS1 sequence. The deletion was predicted to cause a frameshift at codon 882; they referred to the mutation as del882fs/ter937. The normal stop codon at 891 was absent and a new downstream termination codon had been introduced. The predicted protein contained 937 amino acids, 47 more than the normal protein. .0002 WOLFRAM SYNDROME 1 In a consanguineous Japanese family segregating Wolfram syndrome (222300), Inoue et al. (1998) demonstrated that 4 affected sibs were homozygous for a 15-bp deletion in the WFS1 gene resulting in deletion of 5 amino acids, tyr-val-tyr-leu-leu, beginning with residue 508. .0003 WOLFRAM SYNDROME 1 In a Japanese family segregating Wolfram syndrome (222300), Inoue et al. (1998) demonstrated that affected members were homozygous for a 2341C-T transition resulting in a pro724-to-leu (P724L) amino acid substitution. .0004 WOLFRAM SYNDROME 1 In a European family, Inoue et al. (1998) demonstrated that 3 sibs with Wolfram syndrome (222300) were compound heterozygotes for a 2254G-T transversion resulting in a gly695-to-val (G695V) amino acid substitution (inherited from the father); and a 2114G-A transition resulting in a trp648-to-ter (W648X) truncation of the protein, predicted to lack 242 amino acids of the C terminus (inherited from the mother). .0005 WOLFRAM SYNDROME 1 See 222300.0004 and Inoue et al. (1998). .0006 WOLFRAM SYNDROME 1 In an Australian family, Inoue et al. (1998) found apparent homozygosity for a 1681C-T transition (pro504 to leu; P504L) of the WFS1 gene in 3 sibs with Wolfram syndrome (222300). The father was shown to be heterozygous for 1681C-T, but the mother was homozygous 1681C. An unaffected child appeared to be homozygous for 1681C. The mother's chromosome 4, inherited by each child, was thought to harbor a microscopic deletion for WFS1, making the affected offspring hemizygous for the P504L mutation. .0007 WOLFRAM SYNDROME 1 In a 10-year-old Saudi Arabian child with Wolfram syndrome (222300) and first-cousin parents, Inoue et al. (1998) found homozygosity for a 7-bp repeat insertion at nucleotide 1610 (CTGAAGG), resulting in a predicted frameshift and premature termination of the protein at codon 544. .0008 WOLFRAM SYNDROME 1 Strom et al. (1998) found a 9-bp deletion in exon 8 of the WFS1 gene in a 22-year-old female with Wolfram syndrome (222300). The deletion began at nucleotide 1380, counting from the first base of the start codon, and was present in homozygous state. The patient had onset of \ ``diabetes``\ mellitus and \ ``diabetes``\ insipidus at 6 years of age and also had progressive optic atrophy, abnormal audiogram, renal tract abnormalities, retarded sexual maturation, ataxia and nystagmus, and depression. A sister with the same mutation had onset of \ ``diabetes``\ mellitus at 4 years of age, and at the age of 11 years had renal tract abnormalities as the only additional feature. .0009 WOLFRAM SYNDROME 1 In a brother and sister with Wolfram syndrome (222300), Strom et al. (1998) found homozygosity for a splicing mutation in the WFS1 gene: 460+1G-A in the 5-prime splice signal of exon 4. In the brother and sister, \ ``diabetes``\ mellitus began at ages 10 and 9 years, progressive optic atrophy at 14 and 12 years, abnormal audiogram at 13 and 17 years, and \ ``diabetes``\ insipidus at 15 and 15 years, respectively. Renal tract abnormalities were present only in the brother, who at the age of 17 years showed retarded sexual maturation. .0010 WOLFRAM SYNDROME 1 In a 25-year-old female patient with Wolfram syndrome (222300), Strom et al. (1998) found compound heterozygosity for 2 nonsense mutations, gln226 to ter and gln819 to ter (222300.0011) of the WFS1 gene. These mutations were located in exons 6 and 8, respectively. \ ``diabetes``\ mellitus and \ ``diabetes``\ insipidus had their onset at 7 years of age; progressive optic atrophy began at 9 years, abnormal audiogram at 22 years, and renal tract abnormalities at 24 years. The patient also had ataxia and nystagmus. .0011 WOLFRAM SYNDROME 1 See 222300.0010 and Strom et al. (1998). .0012 WOLFRAM SYNDROME 1 Hardy et al. (1999) and Sam et al. (2001) described Wolfram syndrome (222300) with a distinctive phenotype, namely, central respiratory failure: the patients were homozygous for a 4-bp (TCTT) deletion at position 2648-2651 in exon 8 of the WFS1 gene. The deletion caused loss of codon 883 and a frameshift, producing a 949-amino acid WFS1 protein, which was 59 amino acids longer than normal. The mutation changed the last 7 amino acids of the C terminus of the protein, leaving the transmembrane domains intact. In the patient with the 4-bp deletion reported by Hardy et al. (1999), there was severe brainstem atrophy and central respiratory failure requiring tracheostomy. Her affected sister had died at age 28 from brainstem atrophy and central respiratory failure. Five patients (from 3 families) who were heterozygous for the 4-bp deletion did not have respiratory failure. The 33-year-old patient reported by Sam et al. (2001) was diagnosed as having \ ``diabetes``\ mellitus, a neurogenic bladder, and bilateral optic atrophy at the age of 10, 13, and 15, respectively. Audiometry was normal, and there was no evidence of \ ``diabetes``\ insipidus. After an episode of respiratory arrest at age 32, she required intubation, ventilation, and subsequently, tracheostomy. MRI scan showed marked brainstem atrophy. .0013 WOLFRAM SYNDROME 1 Gomez-Zaera et al. (2001) studied 22 Wolfram syndrome (222300) patients from 16 Spanish families for mutations in the WFS1 coding region by SSCP analysis and direct sequencing. Fifty percent of the pedigrees were found to have a single mutation, 67% in homozygosity and 33% in compound heterozygosity. The authors stated that the mutation is a 16-bp insertion in exon 4 at nucleotide 425 and is predicted to produce an aberrant protein; assuming that no splicing alterations occur, translation will follow until residue 251, where a stop codon is created. The high incidence of this mutation in Spanish families may be explained by a founder effect. In 4 patients from 3 Spanish families with Wolfram syndrome, Domenech et al. (2004) identified the 425ins16 mutation, which they referred to as a 16-bp duplication (409dup16). .0014 DEAFNESS, AUTOSOMAL DOMINANT 6 Young et al. (2001) described a 6-generation Canadian family with dominantly inherited progressive hearing loss (600965), in which affected individuals were heterozygous for a 2146G-A transition in WFS1. The mutation resulted in an ala716-to-thr substitution. Affected individuals lacked additional phenotypic features seen in Wolfram syndrome, with the exception of a child who was homozygous for the mutation and also manifested \ ``diabetes``\ mellitus by the age of 3 years. In 2 affected members of a 3-generation Japanese family segregating autosomal dominant nonsyndromic low-frequency sensorineural hearing loss, Fukuoka et al. (2007) identified heterozygosity for the A716T mutation in the WFS1 gene. The mutation was not found in 3 unaffected family members or in 86 controls. Because the same mutation was previously found in a family of European ancestry, the authors suggested that this might represent a mutation hotspot. .0015 DEAFNESS, AUTOSOMAL DOMINANT 6 Bespalova et al. (2001) described a 3-generation American family with low-frequency sensorineural hearing loss (600965). Affected individuals were heterozygous for a T2656C transition in the WFS1 gene, resulting in a leu829-to-pro (L829P) substitution. .0016 DEAFNESS, AUTOSOMAL DOMINANT 6 Bespalova et al. (2001) and Cryns et al. (2002) described patients with low-frequency sensorineural hearing loss (600965) due to a 2096C-T nucleotide change in exon 8 of the WFS1 gene, predicting a thr699-to-met (T699M) protein change. .0017 DEAFNESS, AUTOSOMAL DOMINANT 6 Bespalova et al. (2001) and Cryns et al. (2002) described patients with low-frequency sensorineural hearing loss (600965) due to a 2492G-A transition in exon 8 of the WFS1 gene, predicting a gly831-to-asp (G831D) amino acid change. .0018 DEAFNESS, AUTOSOMAL DOMINANT 6 In a Japanese family in which 20 members had nonsyndromic low-frequency sensorineural hearing loss (600965), Komatsu et al. (2002) demonstrated linkage to chromosome 4p16 and found a novel missense mutation, lys634 to thr (K634T), in the WFS1 gene. The mutation was located in the hydrophobic, extracytoplasmic, juxta-transmembrane region of the WFS1 protein. The mutation site was thought to be related to the milder phenotype (lacking tinnitus) in the Japanese family compared with the findings in 6 previously reported patients with WFS1 mutations (Lesperance et al., 1995; Strom et al., 1998). .0019 WOLFRAM SYNDROME 1 In Wolfram syndrome (222300) patients from 5 different unrelated Italian families, Colosimo et al. (2003) found a 16-bp deletion that removed nucleotides 1362 to 1377, causing a frameshift with premature termination at codon 454. .0020 WOLFRAM-LIKE SYNDROME, AUTOSOMAL DOMINANT In affected members of a 3-generation Danish family with an autosomal dominant Wolfram-like syndrome (WFSL; 614296), Eiberg et al. (2006) identified heterozygosity for a 2590G-A transition in exon 8 of the WFS1 gene, resulting in a glu864-to-lys (E864K) substitution. Affected individuals had optic atrophy, progressive hearing impairment, and impaired \ ``glucose``\ regulation. The mutation was not found in unaffected family members, nor in 2 family members with isolated congenital hearing impairment. In 7 affected members from 2 unrelated Japanese families segregating autosomal dominant nonsyndromic low-frequency sensorineural hearing loss (600965), Fukuoka et al. (2007) identified heterozygosity for the E864K mutation in the WFS1 gene. The mutation was not found in 3 unaffected family members or in 86 controls. Because the same mutation was previously found in a family of European ancestry, the authors suggested that this might represent a mutation hotspot. In a 60-year-old French man with congenital hearing impairment and non\ ``insulin``\ -dependent \ ``diabetes``\ and his 81-year-old mother with deafness, \ ``diabetes``\ , and optic atrophy, Valero et al. (2008) identified heterozygosity for the E864K mutation in the WSF1 gene. The mutation was not found in 100 French controls. The proband, who did not have optic atrophy or any other manifestations of Wolfram syndrome, also carried a 683G-A transition in exon 6 of WSF1, resulting in an arg228-to-gln (R228Q; 606201.0026) substitution at a conserved residue that was not found in controls. .0021 \ ``diabetes``\ MELLITUS, NON\ ``insulin``\ -DEPENDENT, ASSOCIATION WITH In an association study for type 2 \ ``diabetes``\ (125853) involving single-nucleotide polymorphisms (SNPs) in genes with roles in pancreatic beta-cell function, Sandhu et al. (2007) identified association of 2 SNPs in the WFS1 gene, rs10010131 and rs6446482 (602228.0022), with \ ``diabetes``\ risk. Analysis of a pooled study set of 9,533 cases and 11,389 controls achieved a P value of 1.4 x 10(-7) for rs10010131 and a P value of 3.4 x 10(-7) for rs6446482. Both of these SNPs are intronic, with no obvious evidence for biologic function. .0022 \ ``diabetes``\ MELLITUS, NON\ ``insulin``\ -DEPENDENT, ASSOCIATION WITH See 602228.0021 and Sandhu et al. (2007). .0023 DEAFNESS, AUTOSOMAL DOMINANT 6 In 6 affected members of a family with autosomal dominant sensorineural deafness (600965), Hildebrand et al. (2008) identified a heterozygous 2576G-A transition in exon 8 of the WFS1 gene, resulting in an arg859-to-gln (R859Q) substitution in the C-terminal domain. Two affected females had concurrent Crohn disease (see 266600) and Graves disease (275000), respectively. Hildebrand et al. (2008) noted that polymorphisms in the WFS1 gene (see, e.g., 606201.0021) had been associated with autoimmune disease, and suggested that the autoimmune disease in the 2 family members may be related to variants in the WFS1 gene. .0024 WOLFRAM SYNDROME 1 In 20 Lebanese patients from 8 families ascertained with juvenile-onset \ ``insulin``\ -dependent \ ``diabetes``\ (222100), Zalloua et al. (2008) identified homozygosity for a complex mutation in exon 8 of the WFS1 gene, which they designated WFS1(LIB), consisting of a 2289G-A transition, resulting in a val707-to-phe (V707F) substitution, and a 1-bp del (2819delC), resulting in a frameshift predicted to cause premature truncation. The mutations were in complete linkage disequilibrium and were consistently associated with the same haplotype. Eight of the 20 patients were diagnosed with Wolfram syndrome (WFS1; 222300), whereas 10 had only nonsyndromic nonautoimmune \ ``diabetes``\ mellitus (DM); the remaining 2 patients were given an initial diagnosis of nonsyndromic DM that was revised to WFS when they developed optic atrophy during the course of the study. Another Lebanese patient with nonsyndromic DM was found to be compound heterozygous for the complex mutation and an 8-bp deletion in exon 8 of the WFS1 gene (606201.0025), resulting in a frameshift predicted to cause premature truncation. Zalloua et al. (2008) noted that follow-up of these WFS1-mutated nonsyndromic DM patients or a specific study of adult patient populations would be needed to determine whether a subset of the WFS1(LIB) patients are exempted from extrapancreatic manifestations during their lifetime. .0025 WOLFRAM SYNDROME 1 See 606201.0024 and Zalloua et al. (2008). .0026 WOLFRAM-LIKE SYNDROME, AUTOSOMAL DOMINANT See 606201.0020 and Valero et al. (2008). .0027 WOLFRAM-LIKE SYNDROME, AUTOSOMAL DOMINANT In 3 affected members of a Dutch family segregating autosomal dominant deafness and optic neuropathy (Wolfram-like syndrome; 614296), Hogewind et al. (2010) identified heterozygosity for a 2508G-C transversion in exon 8 of the WSF1 gene, resulting in a lys836-to-asn (K836N) substitution at a highly conserved residue within a conserved region of the protein. The mutation was not found in unaffected family members or in 200 European chromosomes. .0028 WOLFRAM-LIKE SYNDROME, AUTOSOMAL DOMINANT In affected members of 6 unrelated families segregating autosomal dominant hearing loss and optic atrophy (Wolfram-like syndrome; 614296), including the Swedish family originally reported by Samuelson (1940), Rendtorff et al. (2011) identified heterozygosity for a 2051C-T transition in exon 8 of the WFS1 gene, resulting in an ala684-to-val (A684V) substitution at a highly conserved residue in the hydrophilic C terminus. The mutation was not found in 298 ethnically matched control chromosomes. Haplotype analysis suggested that the A684V mutation arose independently in the families studied and may thus represent a mutation hotspot. In 5 of the 6 families, there were spouses with isolated deafness, prompting analysis of the GJB2 gene (121011), which revealed that 2 of the probands also carried known SNHL-related mutations in the GJB2 gene (121011.0001 or 121011.0005) inherited from a deaf parent who did not have optic atrophy. In 1 family, the proband's asymptomatic wife carried a 3-bp deletion (1243delGTC; 606201.0029) in the WFS1 gene, resulting in deletion of val415 (V415del); their 2 children were compound heterozygotes for the deletion and A684V mutation, and both were diagnosed with Wolfram syndrome (222300) based on juvenile-onset \ ``diabetes``\ mellitus, optic atrophy, bilateral profound sensorineural hearing loss from birth or infancy, and congenital cataracts. Functional expression analysis in transiently transfected HEK cells demonstrated that both A684V and V415del greatly reduced protein expression compared to wildtype. Rendtorff et al. (2011) noted that A684V had previously been reported in an Italian patient with Wolfram syndrome (Tessa et al., 2001) in compound heterozygosity with a 4-bp deletion (1387delCTCT; 606201.0030) in the WFS1 gene. .0029 WOLFRAM SYNDROME 1 See 606201.0028 and Rendtorff et al. (2011). .0030 WOLFRAM SYNDROME 1 See 606201.0028 and Tessa et al. (2001). .0031 WOLFRAM-LIKE SYNDROME, AUTOSOMAL DOMINANT In a sister and brother and their affected mother from a Caucasian UK family segregating autosomal dominant hearing loss and optic atrophy (Wolfram-like syndrome; 614296), Rendtorff et al. (2011) identified heterozygosity for a 2338G-A transition in exon 8 of the WFS1 gene, resulting in a gly780-to-ser (G780S) substitution at a conserved residue in the hydrophilic C terminus. The mutation was not found in 298 ethnically matched control chromosomes, and functional analysis in transiently transfected HEK cells demonstrated that G780S mildly decreased protein expression compared to wildtype. The 14-year-old sister was reported to have bilateral prelingual profound hearing loss and optic atrophy, with normal plasma \ ``glucose``\ and urine osmolality, and her 9-year-old affected brother had also been diagnosed with autism. Their 48-year-old affected mother also had schizophrenia and had been treated for psychosis; she had an affected brother and sister. The sibs' father, who had isolated sensorineural hearing loss (SNHL), was homozygous for a known SNHL-related mutation in the GJB2 gene (35delG; 121011.0005), and the sibs were both heterozygous for that mutation as well. .. _WFS1 Phenotype: NCBI Phenotypes *************** * \ ``Diabetes``\ mellitus AND insipidus with optic atrophy AND deafness * Gene Reviews * WFS1-Related Disorders * Genetic variant near IRS1 is associated with type 2 \ ``diabetes``\ , \ ``insulin``\ resistance and hyper\ ``insulin``\ emia. * Wolfram-like syndrome, autosomal dominant * Twelve type 2 \ ``diabetes``\ susceptibility loci identified through large-scale association analysis. * \ ``Diabetes``\ mellitus type 2 * OMIM * GTR * NHGRI GWA Catalog .. _WFS1 GO Term: Gene Ontology ************* * endoplasmic reticulum calcium ion homeostasis * negative regulation of sequence-specific DNA binding transcription factor activity * positive regulation of protein ubiquitination * activating transcription factor binding * dendrite * neurological system process * ER overload response * ATPase binding * regulation of apoptotic process * renal water homeostasis * negative regulation of apoptotic process * endoplasmic reticulum unfolded protein response * endoplasmic reticulum * polyubiquitinated misfolded protein transport * ubiquitin protein ligase binding * sensory perception of sound * protein stabilization * response to endoplasmic reticulum stress * endoplasmic reticulum membrane * transporter activity * activation of signaling protein activity involved in unfolded protein response * positive regulation of growth * positive regulation of calcium ion transport * \ ``glucose``\ homeostasis * negative regulation of programmed cell death * protein maturation by protein folding * positive regulation of protein metabolic process * positive regulation of proteolysis * visual perception * ER-associated protein catabolic process * integral to endoplasmic reticulum membrane * kidney development * negative regulation of neuron apoptotic process * calcium ion homeostasis .. _WFS1 Pathway: KEGG Pathways ************* * `Protein processing in endoplasmic reticulum `_ .. _WFS1 GeneRIF: GeneRIFs ******** * WFS1 gene is associated with autistic traits, empathy and Asperger syndrome. [`PMID 19598235`_] * Mutations in one single gene, Wolfram syndrome 1 (WFS1), have been reported to account for most familial cases with low-frequency hearing loss. [`PMID 15912360`_] * May be a candidate gene for type 2 \ ``diabetes``\ . [`PMID 18197395`_] * Observational study and genome-wide association study of gene-disease association. (HuGE Navigator) [`PMID 19734900`_] * In this study we analyzed the phenotype of a large Hungarian family with LFSNHI and linkage to DFNA6. The family contains 14 affected persons. [`PMID 14968315`_] * WFS1 mutations lead to drastically reduced steady-state levels of wolframin. [`PMID 16806192`_] * Meta-analysis and HuGE review of gene-disease association. (HuGE Navigator) [`PMID 19602701`_] * Wolframin has a role in the regulation of intracellular Ca2+ homeostasis [`PMID 14527944`_] * mutational analysis of the WFS1 coding region in 19 Italian Wolfram syndrome patients and 25 relatives, using a DHPLC-based protocol [`PMID 12754709`_] * WFS1 minimal promoter contains two DNA binding motifs (GC boxes) for the transcription factors Sp1/3/4 and binding of both Sp1 and Sp3 was demonstrated at both motifs in vitro and in vivo. [`PMID 16965966`_] * The p.A684V missense mutation in the WFS1 gene is a frequent cause of autosomal dominant optic atrophy and hearing impairment. [`PMID 21538838`_] * A WFS1 haplotype consisting of the minor alleles of rs752854, rs10010131, and rs734312 shows a protective role against type 2 \ ``diabetes``\ in Russian patients [`PMID 21713316`_] * found a significantly higher frequency of the 611R/611R genotype in suicide completers. Scores of impulsivity and novelty seeking were higher in subjects with the associated genotype, suggesting a role for WFS1 in the pathophysiology of impulsive suicide [`PMID 12707947`_] * Observational study of gene-disease association, gene-gene interaction, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator) [`PMID 20879858`_] * six highly correlated single nucleotide polymorphisms that show strong and comparable associations with risk of type 2 \ ``diabetes``\ [`PMID 20028947`_] * These results support the hypothesis that the WFS1 gene is involved in the genetic predisposition for mood disorders. [`PMID 15473915`_] * The most frequent haplotype at the haplotype block containing the WFS1 gene modulated \ ``insulin``\ secretion and was associated with an increased risk of type 2 \ ``diabetes``\ . [`PMID 21127832`_] * found no evidence for a substantial effect of WFS1 polymorphisms on risk of type 2 \ ``diabetes``\ or clinical characteristics of diabetic subjects in Japanese population [`PMID 19258739`_] * genetic variation of Wolfram syndrome type 1 gene was a more crucial factor than other genes in causing hearing loss. [`PMID 22240535`_] * Observational study of gene-disease association. (HuGE Navigator) [`PMID 20816152`_] * The WFS1 gene is located on the short arm of chromosome 4 in Wolfram syndrome. [`PMID 18566338`_] * the pathogenesis of Wolfram syndrome involves chronic ER stress in pancreatic beta-cells caused by the loss of function of WFS1 [`PMID 16195229`_] * Molecular analysis of WFS1 in seven families with Wolfram syndrome identified eight different mutations; one was a de novo mutation occurring independently in 2 families, whereas the remaining ones were inherited. [`PMID 16151413`_] * Affinity Capture-MS; Affinity Capture-Western [`PMID 21906983`_] * Replication of the previously reported associations between SNPs at this locus and the risk of type 2 \ ``diabetes``\ . [`PMID 18040659`_] * This report of two novel WFS1 mutations expands the molecular spectrum of Wolfram syndrome. [`PMID 18660851`_] * report a consanguineous family with three siblings affected by Wolfram syndrome. A homozygous single base pair deletion (c.877delC, L293fsX303) was found in the WFS1 gene in all three affected siblings [`PMID 21823543`_] * The relative risk of psychiatric hospitalization for depression was estimated to be 7.1 (95% CI 1.9-26.6) for carriers of a single wolframin mutation compared to noncarriers. [`PMID 15852062`_] * Observational study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator) [`PMID 20628086`_] * Mutations in WFS1 are one cause of non-syndromic low frequency sensorineural hearing loss. [`PMID 16408729`_] * a novel heterozygous missense mutation in exon 8 of WFS1 (i.e., Y669H) which is likely responsible for the low-frequency sensorineural hearing loss (LFSNHL) phenotype in a Taiwanese family was discovered [`PMID 17517145`_] * Mutations in the WFS1 gene that cause low-frequency sensorineural hearing loss are small non-inactivating mutations. [`PMID 12073007`_] * This study describes the phenotype of a family with autosomal dominant optic neuropathy and hearing impairment associated with a novel missense mutation in WFS1. [`PMID 20069065`_] * Nine different mutations in WFS1 (five of them novel) were identified in nine Wolfram syndrome patients. [`PMID 21564155`_] * Overview of the spectrum of WFS1 mutations in Wolfram syndrome, nonsyndromic low frequency sensorineural hearing impairment,\ ``diabetes``\ mellitus, and psychiatric disease. [`PMID 12955714`_] * Study identifies an interaction between Wolframin and Na+/K+ ATPase beta1 subunit in transfected Cos7 cells, and between endogenous proteins in placental, neuroblastoma and MIN6 pancreatic beta-cell lines. [`PMID 17947299`_] * In all affected family members analysed, we detected a missense mutation in WFS1 (K705N) and therefore confirm the finding that the majority of mutations responsible for LFSNHI are missense mutations which localise to the C-terminal domain of the protein. [`PMID 12650912`_] * Observational study of gene-disease association, gene-gene interaction, and gene-environment interaction. (HuGE Navigator) [`PMID 20889853`_] * WFS1 is not a major susceptibility gene for the development of psychiatric disorders in subjects with Wolfram syndrome. [`PMID 12605098`_] * The family described with autosomal dominant inheritance of K836T of the WFS1 gene demonstrates a progressive hearing loss in the lower frequencies. [`PMID 19877185`_] * a novel heterozygous missense mutation in exon 8 of WFS1 predicting a p.R685P amino acid substitution that is likely to underlie the low frequency sensorineural hearing loss phenotype in the American family [`PMID 18518985`_] * Study show that polymorphisms in WFS1 were associated with type 2 \ ``diabetes``\ risk in the studied population. [`PMID 18694974`_] * Results reported eight novel WFS1 mutations in Wolfram syndrome. [`PMID 17568405`_] * Observational study of gene-disease association and gene-environment interaction. (HuGE Navigator) [`PMID 20802253`_] * A novel missense mutation in WFS1 was identified which caused Wolfram syndrome and may also be linked to autoimmune diseases. [`PMID 18688868`_] * Type 2 \ ``diabetes``\ -associated risk alleles of WFS1 are associated with estimates of a decreased pancreatic beta cell function among middle-aged individuals with abnormal \ ``glucose``\ regulation [`PMID 18568334`_] * Here we investigate, for the first time, the molecular mechanisms that cause loss-of-function of wolframin in affected individuals. [`PMID 12913071`_] * In a pooled analysis comprising 9,533 cases and 11,389 controls, SNPs in WFS1 were strongly associated with common type 2 \ ``diabetes``\ risk. [`PMID 17603484`_] * A new homozygous WFS1 mutation causing causing Wolfram syndrome is identified in a large inbred Turkish family. [`PMID 21968327`_] * Observational study of gene-disease association and gene-gene interaction. (HuGE Navigator) [`PMID 20571754`_] * maternally inherited combination of \ ``diabetes``\ mellitus and hearing impairment in three members of a family was found to be associated with autosomal dominant transmission of the E864K mutation of the WFS1 gene [`PMID 18544103`_] * The WFS1 locus strongly contributes to juvenile-onset \ ``diabetes``\ in Lebanon in Wolfram syndrome and non-syndromic non-autoimmune \ ``diabetes``\ mellitus detected by linkage analysis; effect varies by allele. [`PMID 18806274`_] * Two individuals who had heterozygosity of GJB2 mutations and heterozygosity of WFS1 mutations showed low-frequency hearing loss. One individual who had homozygosity of GJB2 mutation without WFS1 mutation had moderate, gradual high tone hearing loss. [`PMID 22498363`_] * This study presents a six-generation family from Hungary with nonsyndromic, post-lingual, bilateral, symmetric, progressive LFSNHI, that discloses positive linkage to the DFNA6 region. [`PMID 16043233`_] * Genome-wide association datase revealed that a strong linkage disequilibrium with the three WFS1 single nucleotide polymorphisms was associated with type 2 \ ``diabetes``\ . [`PMID 18060660`_] * Two-hybrid [`PMID 16169070`_] * A common genetic variant in WFS1 specifically impairs GLP-1-induced \ ``insulin``\ secretion independently of \ ``insulin``\ sensitivity [`PMID 19330314`_] * a role for WFS1 in the negative regulation of ER stress signaling and in the pathogenesis of diseases involving chronic, unresolvable ER stress, such as pancreatic beta cell death in \ ``diabetes``\ . [`PMID 20160352`_] * Affinity Capture-Western [`PMID 20160352`_] * Affinity Capture-Western [`PMID 20160352`_] * Affinity Capture-Western [`PMID 20160352`_] * Four new polymorphisms associated with Wolfram syndrome. Not all patients have full syndrome. [`PMID 12107816`_] * The causal relationship between WFS1 missense mutation and deafness was supported by two observations based on haplotype and mutation analysis of the kindred. [`PMID 11709538`_] * most causative changes identified in the WFS1 gene occurred in exon 8, and only one was identified outside this region in exon 4 in patients with Wolfram syndrome [`PMID 15277431`_] * one-third (3 out of 9) autosomal dominant low frequency sensorineural hearing loss(LFSNHL) families had mutations in WFS1, indicating that in non-syndromic hearing loss WFS1 is restrictively & commonly found within autosomal dominant LFSNHL families [`PMID 17492394`_] * Did not find evidence of an increased incidence of WFS carriers in the suicide panel and concluded that WFS1 carrier status is not a significant contributor to suicide in the general population. [`PMID 11920861`_] * the HNF4A and WFS1 risk alleles predispose to development of type 2 \ ``diabetes``\ in an Ashkenazi Jewish population [`PMID 20361036`_] * Five different heterozygous missense mutations (T699M, A716T, V779M, L829P, G831D) in the WFS1 gene found in six low frequency sensorineural hearing loss (LFSNHL) families. [`PMID 11709537`_] * WFS1 is the gene responsible for autosomal dominant low-frequency sensorineural hearing loss in a Chinese family, as well as in a sporadic case. These WFS1 mutations are not present in unaffected control subjects. [`PMID 21356526`_] * WFS1 is the major gene involved in Wolfram syndrome in Brazilian patients and most mutations are concentrated in exon 8 [`PMID 19042979`_] * WFS1 protein participates in the regulation of cellular Ca(2+) homeostasis, at least partly, by modulating the filling state of the ER Ca(2+) store [`PMID 16989814`_] * A nine nucleotide insertional mutation in two members of a family with Wolfram syndrome. [`PMID 16005363`_] * Novel mutations in the wolframin gene are identified that are associated with non-immunogenic \ ``diabetes``\ mellitus and a progressive atrophy of the optic nerve. [`PMID 21143470`_] * Two-hybrid [`PMID 21900206`_] * Missense mutations within a defined region are associated with dominant low-frequency hearing loss (DFNA6/14/38), while more severe mutations spanning WFS1 are found in Wolfram syndrome patients. [`PMID 16550584`_] * The H611R polymorphism of Wolframin gene was associated with mood disorders but not suicidal behavior, aggressive/impulsive traits or suicidality in first-degree relatives. [`PMID 19328217`_] * The wolframin His611Arg polymorphism influences medication overuse headache. [`PMID 17719176`_] * ER stress induces Smurf1 degradation and WFS1 up-regulation [`PMID 21454619`_] * Affinity Capture-Western; Reconstituted Complex; Two-hybrid [`PMID 21454619`_] * Their past medical history revealed \ ``diabetes``\ mellitus and deafness since childhood. It was confirmed by molecular analysis, which evidenced composite WFS1 heterozygous mutations inherited from both their mother and father. [`PMID 21632151`_] * Observational study and meta-analysis of gene-disease association. (HuGE Navigator) [`PMID 20490451`_] * This study does not support the involvement of tyrosine hydroxylase, catechol-O-methyl transferase and Wolfram syndrome 1 polymorphisms in mood disorders. [`PMID 12782971`_] .. _PMID 19598235: http://www.ncbi.nlm.nih.gov/pubmed/19598235 .. _PMID 15912360: http://www.ncbi.nlm.nih.gov/pubmed/15912360 .. _PMID 18197395: http://www.ncbi.nlm.nih.gov/pubmed/18197395 .. _PMID 19734900: http://www.ncbi.nlm.nih.gov/pubmed/19734900 .. _PMID 14968315: http://www.ncbi.nlm.nih.gov/pubmed/14968315 .. _PMID 16806192: http://www.ncbi.nlm.nih.gov/pubmed/16806192 .. _PMID 19602701: http://www.ncbi.nlm.nih.gov/pubmed/19602701 .. _PMID 14527944: http://www.ncbi.nlm.nih.gov/pubmed/14527944 .. _PMID 12754709: http://www.ncbi.nlm.nih.gov/pubmed/12754709 .. _PMID 16965966: http://www.ncbi.nlm.nih.gov/pubmed/16965966 .. _PMID 21538838: http://www.ncbi.nlm.nih.gov/pubmed/21538838 .. _PMID 21713316: http://www.ncbi.nlm.nih.gov/pubmed/21713316 .. _PMID 12707947: http://www.ncbi.nlm.nih.gov/pubmed/12707947 .. _PMID 20879858: http://www.ncbi.nlm.nih.gov/pubmed/20879858 .. _PMID 20028947: http://www.ncbi.nlm.nih.gov/pubmed/20028947 .. _PMID 15473915: http://www.ncbi.nlm.nih.gov/pubmed/15473915 .. _PMID 21127832: http://www.ncbi.nlm.nih.gov/pubmed/21127832 .. _PMID 19258739: http://www.ncbi.nlm.nih.gov/pubmed/19258739 .. _PMID 22240535: http://www.ncbi.nlm.nih.gov/pubmed/22240535 .. _PMID 20816152: http://www.ncbi.nlm.nih.gov/pubmed/20816152 .. _PMID 18566338: http://www.ncbi.nlm.nih.gov/pubmed/18566338 .. _PMID 16195229: http://www.ncbi.nlm.nih.gov/pubmed/16195229 .. _PMID 16151413: http://www.ncbi.nlm.nih.gov/pubmed/16151413 .. _PMID 21906983: http://www.ncbi.nlm.nih.gov/pubmed/21906983 .. _PMID 18040659: http://www.ncbi.nlm.nih.gov/pubmed/18040659 .. _PMID 18660851: http://www.ncbi.nlm.nih.gov/pubmed/18660851 .. _PMID 21823543: http://www.ncbi.nlm.nih.gov/pubmed/21823543 .. _PMID 15852062: http://www.ncbi.nlm.nih.gov/pubmed/15852062 .. _PMID 20628086: http://www.ncbi.nlm.nih.gov/pubmed/20628086 .. _PMID 16408729: http://www.ncbi.nlm.nih.gov/pubmed/16408729 .. _PMID 17517145: http://www.ncbi.nlm.nih.gov/pubmed/17517145 .. _PMID 12073007: http://www.ncbi.nlm.nih.gov/pubmed/12073007 .. _PMID 20069065: http://www.ncbi.nlm.nih.gov/pubmed/20069065 .. _PMID 21564155: http://www.ncbi.nlm.nih.gov/pubmed/21564155 .. _PMID 12955714: http://www.ncbi.nlm.nih.gov/pubmed/12955714 .. _PMID 17947299: http://www.ncbi.nlm.nih.gov/pubmed/17947299 .. _PMID 12650912: http://www.ncbi.nlm.nih.gov/pubmed/12650912 .. _PMID 20889853: http://www.ncbi.nlm.nih.gov/pubmed/20889853 .. _PMID 12605098: http://www.ncbi.nlm.nih.gov/pubmed/12605098 .. _PMID 19877185: http://www.ncbi.nlm.nih.gov/pubmed/19877185 .. _PMID 18518985: http://www.ncbi.nlm.nih.gov/pubmed/18518985 .. _PMID 18694974: http://www.ncbi.nlm.nih.gov/pubmed/18694974 .. _PMID 17568405: http://www.ncbi.nlm.nih.gov/pubmed/17568405 .. _PMID 20802253: http://www.ncbi.nlm.nih.gov/pubmed/20802253 .. _PMID 18688868: http://www.ncbi.nlm.nih.gov/pubmed/18688868 .. _PMID 18568334: http://www.ncbi.nlm.nih.gov/pubmed/18568334 .. _PMID 12913071: http://www.ncbi.nlm.nih.gov/pubmed/12913071 .. _PMID 17603484: http://www.ncbi.nlm.nih.gov/pubmed/17603484 .. _PMID 21968327: http://www.ncbi.nlm.nih.gov/pubmed/21968327 .. _PMID 20571754: http://www.ncbi.nlm.nih.gov/pubmed/20571754 .. _PMID 18544103: http://www.ncbi.nlm.nih.gov/pubmed/18544103 .. _PMID 18806274: http://www.ncbi.nlm.nih.gov/pubmed/18806274 .. _PMID 22498363: http://www.ncbi.nlm.nih.gov/pubmed/22498363 .. _PMID 16043233: http://www.ncbi.nlm.nih.gov/pubmed/16043233 .. _PMID 18060660: http://www.ncbi.nlm.nih.gov/pubmed/18060660 .. _PMID 16169070: http://www.ncbi.nlm.nih.gov/pubmed/16169070 .. _PMID 19330314: http://www.ncbi.nlm.nih.gov/pubmed/19330314 .. _PMID 20160352: http://www.ncbi.nlm.nih.gov/pubmed/20160352 .. _PMID 12107816: http://www.ncbi.nlm.nih.gov/pubmed/12107816 .. _PMID 11709538: http://www.ncbi.nlm.nih.gov/pubmed/11709538 .. _PMID 15277431: http://www.ncbi.nlm.nih.gov/pubmed/15277431 .. _PMID 17492394: http://www.ncbi.nlm.nih.gov/pubmed/17492394 .. _PMID 11920861: http://www.ncbi.nlm.nih.gov/pubmed/11920861 .. _PMID 20361036: http://www.ncbi.nlm.nih.gov/pubmed/20361036 .. _PMID 11709537: http://www.ncbi.nlm.nih.gov/pubmed/11709537 .. _PMID 21356526: http://www.ncbi.nlm.nih.gov/pubmed/21356526 .. _PMID 19042979: http://www.ncbi.nlm.nih.gov/pubmed/19042979 .. _PMID 16989814: http://www.ncbi.nlm.nih.gov/pubmed/16989814 .. _PMID 16005363: http://www.ncbi.nlm.nih.gov/pubmed/16005363 .. _PMID 21143470: http://www.ncbi.nlm.nih.gov/pubmed/21143470 .. _PMID 21900206: http://www.ncbi.nlm.nih.gov/pubmed/21900206 .. _PMID 16550584: http://www.ncbi.nlm.nih.gov/pubmed/16550584 .. _PMID 19328217: http://www.ncbi.nlm.nih.gov/pubmed/19328217 .. _PMID 17719176: http://www.ncbi.nlm.nih.gov/pubmed/17719176 .. _PMID 21454619: http://www.ncbi.nlm.nih.gov/pubmed/21454619 .. _PMID 21632151: http://www.ncbi.nlm.nih.gov/pubmed/21632151 .. _PMID 20490451: http://www.ncbi.nlm.nih.gov/pubmed/20490451 .. _PMID 12782971: http://www.ncbi.nlm.nih.gov/pubmed/12782971 .. _WFS1 Pubmed: PubMed Articles *************** *Recent articles:* * Minami SB et al. "Comorbidity of GJB2 and WFS1 mutations in one family." Gene. 2012 Jun 15;501(2):193-7. `PMID 22498363`_ * Yuca SA et al. "Rapidly progressive renal disease as part of Wolfram syndrome in a large inbred Turkish family due to a novel WFS1 mutation (p.Leu511Pro)." Eur J Med Genet. 2012 Jan;55(1):37-42. `PMID 21968327`_ * Yuan BC et al. "A predictive model of the association between gene polymorphism and the risk of noise-induced hearing loss caused by gunfire noise." J Chin Med Assoc. 2012 Jan;75(1):36-9. `PMID 22240535`_ * Zmyslowska A et al. "Wolfram syndrome in the Polish population: novel mutations and genotype-phenotype correlation." Clin Endocrinol (Oxf). 2011 Nov;75(5):636-41. `PMID 21564155`_ * Kim W et al. "Systematic and quantitative assessment of the ubiquitin-modified proteome." Mol Cell. 2011 Oct 21;44(2):325-40. `PMID 21906983`_ * Conart JB et al. "[Wolfram syndrome: clinical and genetic analysis in two sisters]." J Fr Ophtalmol. 2011 Oct;34(8):543-6. `PMID 21632151`_ * Vinayagam A et al. "A directed protein interaction network for investigating intracellular signal transduction." Sci Signal. 2011 Sep 6;4(189):rs8. `PMID 21900206`_ * Pitt K et al. "A single base-pair deletion in the WFS1 gene causes Wolfram syndrome." J Pediatr Endocrinol Metab. 2011;24(5-6):389-91. `PMID 21823543`_ * Rendtorff ND et al. "Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment." Am J Med Genet A. 2011 Jun;155A(6):1298-313. `PMID 21538838`_ * Chistiakov DA et al. "A WFS1 haplotype consisting of the minor alleles of rs752854, rs10010131, and rs734312 shows a protective role against type 2 diabetes in Russian patients." Rev Diabet Stud. 2010 Winter;7(4):285-92. `PMID 21713316`_ .. _PMID 22498363: http://www.ncbi.nlm.nih.gov/pubmed/22498363 .. _PMID 21900206: http://www.ncbi.nlm.nih.gov/pubmed/21900206 .. _PMID 21823543: http://www.ncbi.nlm.nih.gov/pubmed/21823543 .. _PMID 21968327: http://www.ncbi.nlm.nih.gov/pubmed/21968327 .. _PMID 21538838: http://www.ncbi.nlm.nih.gov/pubmed/21538838 .. _PMID 21632151: http://www.ncbi.nlm.nih.gov/pubmed/21632151 .. _PMID 21713316: http://www.ncbi.nlm.nih.gov/pubmed/21713316 .. _PMID 21564155: http://www.ncbi.nlm.nih.gov/pubmed/21564155 .. _PMID 22240535: http://www.ncbi.nlm.nih.gov/pubmed/22240535 .. _PMID 21906983: http://www.ncbi.nlm.nih.gov/pubmed/21906983 *Top Pubmed articles linked to gene WFS1 matching any search term:* * Rigoli L et al. "Wolfram syndrome 1 and Wolfram syndrome 2." Curr Opin Pediatr. 2012 Aug;24(4):512-7. `PMID 22790102`_ * Hershey T et al. "Early Brain Vulnerability in Wolfram Syndrome." PLoS One. 2012;7(7):e40604. `PMID 22792385`_ * Haghighi A et al. "Identification of homozygous WFS1 mutations (p.Asp211Asn, p.Gln486*) causing severe Wolfram syndrome and first report of male fertility." Eur J Hum Genet. 2012 Jul 11;. `PMID 22781099`_ * Elli FM et al. "A new structural rearrangement associated to Wolfram syndrome in a child with a partial phenotype." Gene. 2012 Jul 4;. `PMID 22771918`_ * Franceschini N et al. "The association of genetic variants of type 2 diabetes with kidney function." Kidney Int. 2012 Jul;82(2):220-5. `PMID 22513821`_ * Linder K et al. "Allele summation of diabetes risk genes predicts impaired glucose tolerance in female and obese individuals." PLoS One. 2012;7(6):e38224. `PMID 22768041`_ * Johansson S et al. "Exome sequencing and genetic testing for MODY." PLoS One. 2012;7(5):e38050. `PMID 22662265`_ * Smushkin G et al. "Diabetes-associated common genetic variation and its association with GLP-1 concentrations and response to exogenous GLP-1." Diabetes. 2012 May;61(5):1082-9. `PMID 22461567`_ * Cauchi S et al. "European genetic variants associated with type 2 diabetes in North African Arabs." Diabetes Metab. 2012 Mar 29;. `PMID 22463974`_ * Saxena R et al. "Polycystic ovary syndrome is not associated with genetic variants that mark risk of type 2 diabetes." Acta Diabetol. 2012 Mar 3;. `PMID 22389004`_ * Rendtorff ND et al. "Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment." Am J Med Genet A. 2011 Jun;155A(6):1298-313. `PMID 21538838`_ * Chistiakov DA et al. "A WFS1 haplotype consisting of the minor alleles of rs752854, rs10010131, and rs734312 shows a protective role against type 2 diabetes in Russian patients." Rev Diabet Stud. 2010 Winter;7(4):285-92. `PMID 21713316`_ * Alimadadi A et al. "Novel mutations of wolframin: a report with a look at the protein structure." Clin Genet. 2011 Jan;79(1):96-9. `PMID 21143470`_ * Rotger M et al. "Impact of single nucleotide polymorphisms and of clinical risk factors on new‐onset diabetes mellitus in HIV‐infected individuals." Clin Infect Dis. 2010 Nov 1;51(9):1090-8. `PMID 20879858`_ * Voight BF et al. "Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis." Nat Genet. 2010 Jul;42(7):579-89. `PMID 20581827`_ * Ruchat SM et al. "Evidence of interaction between type 2 diabetes susceptibility genes and dietary fat intake for adiposity and glucose homeostasis-related phenotypes." J Nutrigenet Nutrigenomics. 2009;2(4-5):225-34. `PMID 20215779`_ * Fawcett KA et al. "Detailed investigation of the role of common and low-frequency WFS1 variants in type 2 diabetes risk." Diabetes. 2010 Mar;59(3):741-6. `PMID 20028947`_ * Schulze MB et al. "Use of multiple metabolic and genetic markers to improve the prediction of type 2 diabetes: the EPIC-Potsdam Study." Diabetes Care. 2009 Nov;32(11):2116-9. `PMID 19720844`_ * Haupt A et al. "The inhibitory effect of recent type 2 diabetes risk loci on insulin secretion is modulated by insulin sensitivity." J Clin Endocrinol Metab. 2009 May;94(5):1775-80. `PMID 19258404`_ * Wasson J et al. "Candidate gene studies reveal that the WFS1 gene joins the expanding list of novel type 2 diabetes genes." Diabetologia. 2008 Mar;51(3):391-3. `PMID 18197395`_ .. _PMID 22792385: http://www.ncbi.nlm.nih.gov/pubmed/22792385 .. _PMID 19720844: http://www.ncbi.nlm.nih.gov/pubmed/19720844 .. _PMID 22790102: http://www.ncbi.nlm.nih.gov/pubmed/22790102 .. _PMID 22513821: http://www.ncbi.nlm.nih.gov/pubmed/22513821 .. _PMID 22461567: http://www.ncbi.nlm.nih.gov/pubmed/22461567 .. _PMID 22781099: http://www.ncbi.nlm.nih.gov/pubmed/22781099 .. _PMID 18197395: http://www.ncbi.nlm.nih.gov/pubmed/18197395 .. _PMID 22768041: http://www.ncbi.nlm.nih.gov/pubmed/22768041 .. _PMID 20581827: http://www.ncbi.nlm.nih.gov/pubmed/20581827 .. _PMID 22389004: http://www.ncbi.nlm.nih.gov/pubmed/22389004 .. _PMID 22463974: http://www.ncbi.nlm.nih.gov/pubmed/22463974 .. _PMID 21143470: http://www.ncbi.nlm.nih.gov/pubmed/21143470 .. _PMID 19258404: http://www.ncbi.nlm.nih.gov/pubmed/19258404 .. _PMID 22771918: http://www.ncbi.nlm.nih.gov/pubmed/22771918 .. _PMID 21538838: http://www.ncbi.nlm.nih.gov/pubmed/21538838 .. _PMID 21713316: http://www.ncbi.nlm.nih.gov/pubmed/21713316 .. _PMID 20215779: http://www.ncbi.nlm.nih.gov/pubmed/20215779 .. _PMID 22662265: http://www.ncbi.nlm.nih.gov/pubmed/22662265 .. _PMID 20879858: http://www.ncbi.nlm.nih.gov/pubmed/20879858 .. _PMID 20028947: http://www.ncbi.nlm.nih.gov/pubmed/20028947