Affinage

WFS1

Wolframin · UniProt O76024

Length
890 aa
Mass
100.3 kDa
Annotated
2026-04-28
100 papers in source corpus 18 papers cited in narrative 18 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WFS1 (wolframin) is an ER-resident transmembrane glycoprotein that functions as a critical regulator of ER homeostasis, Ca²⁺ signaling, and mitochondria-associated membrane (MAM) integrity across multiple cell types. WFS1 is transcriptionally induced by ER stress through IRE1 and PERK pathways and acts within the unfolded protein response to protect pancreatic β-cells from ER stress–mediated apoptosis; its loss causes chronic ER stress with dilated ER, elevated BiP/phospho-eIF2α, and progressive β-cell death exacerbated by increased insulin demand (PMID:16195229, PMID:19190890). Beyond ER quality control, WFS1 localizes to secretory granules where it regulates intragranular acidification and insulin granule docking (PMID:21199859), interacts with VDAC1 at MAMs to sustain ER-to-mitochondria Ca²⁺ transfer and mitochondrial bioenergetics (PMID:37163979, PMID:38651637), and facilitates Na⁺/K⁺-ATPase β1 subunit trafficking in stria vascularis to maintain the endocochlear potential (PMID:37386014). Loss-of-function and dominant-negative mutations in WFS1 cause Wolfram syndrome, characterized by diabetes mellitus, optic atrophy, sensorineural deafness, and neurodegeneration, with disease mechanisms converging on dysregulated Ca²⁺ homeostasis, impaired mitochondrial function, and pro-inflammatory signaling via PERK/IRE1α (PMID:28271591, PMID:35399956, PMID:24823368).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2003 Medium

    Establishing that WFS1/wolframin is an ER-resident glycoprotein expressed in ion-transporting tissues resolved the basic subcellular localization question and suggested a role in ion homeostasis.

    Evidence Immunohistochemistry with ER co-markers in mouse inner ear

    PMID:12649740

    Open questions at the time
    • No direct functional assay for ion transport activity
    • Localization limited to inner ear tissue
  2. 2005 High

    Demonstrating that WFS1 is transcriptionally induced by ER stress through IRE1/PERK and that its knockdown causes ER stress in β-cells established WFS1 as a functional component of the unfolded protein response, not merely an ER-resident bystander.

    Evidence ER stress induction assays, siRNA knockdown in β-cell lines, pharmacological inhibition of IRE1 and PERK

    PMID:16195229

    Open questions at the time
    • Molecular mechanism by which WFS1 alleviates ER stress not identified
    • No direct enzymatic or channel activity demonstrated
  3. 2008 Medium

    Mapping WFS1 expression to specific brain regions (central amygdala, hippocampal CA1, magnocellular neurosecretory neurons, auditory pathway) provided a neuroanatomical basis for the neuropsychiatric and sensory features of Wolfram syndrome.

    Evidence Immunohistochemistry and lacZ reporter in Wfs1 KO mouse brain

    PMID:18551525

    Open questions at the time
    • No cell-type-specific functional consequence of WFS1 loss tested in these regions
    • Expression pattern does not distinguish cell-autonomous from non-autonomous roles
  4. 2009 High

    Showing that Wfs1-null β-cells undergo ER stress–mediated apoptosis with dilated ER under high insulin demand established the in vivo pathogenic mechanism linking WFS1 loss to diabetes.

    Evidence Wfs1−/− × Ay/a obese mice; EM of ER morphology, BiP/p-eIF2α immunoblots, TUNEL, pioglitazone rescue

    PMID:19190890

    Open questions at the time
    • Direct biochemical substrate or binding partner of WFS1 in ER quality control not identified
    • Pioglitazone rescue is indirect (reduces insulin demand) rather than targeting WFS1 directly
  5. 2011 High

    Discovering WFS1 on secretory granules and showing that its loss reduces intragranular acidification and granule docking expanded the functional role of WFS1 beyond ER stress to insulin granule maturation and exocytosis.

    Evidence Immunofluorescence, EM, DAMP acidotrophic dye assay, proinsulin radioimmunoassay in Wfs1-null mice

    PMID:21199859

    Open questions at the time
    • Mechanism by which WFS1 regulates granule pH unknown (channel, pump, or indirect)
    • Whether granule localization is ER-derived or independent trafficking is unresolved
  6. 2014 Medium

    Demonstrating progressive optic pathway dysfunction with ER stress marker elevation in Wfs1-null retinas provided the first direct mechanistic link between WFS1 deficiency and optic atrophy, a cardinal Wolfram syndrome feature.

    Evidence Visual evoked potentials and electroretinograms in Wfs1−/− mice aged 3–12 months; BiP/PDI/IRE1α immunolabeling in retina

    PMID:24823368

    Open questions at the time
    • Specific retinal cell type(s) driving degeneration not determined
    • Contribution of Ca²⁺ dysregulation vs. ER stress in retinal pathology not dissected
  7. 2017 Medium

    Showing that a dominant WFS1 mutation constitutively activates ATF6α and reduces SERCA2b expression linked WFS1 to ER Ca²⁺ store regulation, establishing a mechanistic connection between WFS1 and ER/cytosolic Ca²⁺ homeostasis.

    Evidence Luciferase reporters for ATF6α and NFAT; RT-PCR for SERCA2b; transfection of mutant vs. WT WFS1

    PMID:28271591

    Open questions at the time
    • Direct physical interaction between WFS1 and SERCA2b not demonstrated
    • Single dominant mutation studied; generalizability to all WFS1 mutations uncertain
  8. 2018 Medium

    Drosophila wfs1 knockdown causing age-dependent neurodegeneration with sensitivity to oxidative stress and excitotoxicity, rescuable by riluzole, demonstrated evolutionary conservation and implicated glutamate excitotoxicity in WFS1-linked neurodegeneration.

    Evidence Drosophila wfs1 RNAi in neurons/glia; behavioral and survival assays; riluzole pharmacological rescue

    PMID:29357349

    Open questions at the time
    • Mechanism of riluzole rescue not defined at WFS1 pathway level
    • Invertebrate model—direct translation to human WFS1 neurobiology not confirmed
  9. 2022 Medium

    Revealing that WFS1 deficiency triggers pro-inflammatory cytokine expression in β-cells and immune cells via PERK/IRE1α, with M1-macrophage infiltration of islets in vivo, established inflammation as a pathogenic axis downstream of WFS1 loss, beyond ER stress and Ca²⁺ dysregulation.

    Evidence WFS1 siRNA in β-cell lines and PBMCs; PERK/IRE1α inhibitors; cytokine ELISA; IHC of Wfs1 KO islets; flow cytometry of T-cell subsets

    PMID:33693650 PMID:35399956

    Open questions at the time
    • Whether inflammation is a driver or consequence of β-cell death is unresolved
    • PBMC data from single Wolfram patient lacks statistical power
  10. 2023 High

    Identifying WFS1–VDAC1 interaction at MAMs and showing that its disruption impairs mitochondrial Ca²⁺ uptake, bioenergetics, and neuronal viability—rescuable by WFS1 overexpression—established a direct MAM-based mechanism for Wolfram neurodegeneration.

    Evidence Reciprocal Co-IP of WFS1 and VDAC1; hiPSC-derived neurons from Wolfram patients; WFS1 rescue; OCR and Ca²⁺ assays; confocal MAM imaging

    PMID:37163979

    Open questions at the time
    • Stoichiometry and structural basis of the WFS1–VDAC1 complex unknown
    • Whether MAM defect is upstream or parallel to ER stress phenotype not resolved
  11. 2023 High

    Demonstrating that the WFS1-E864K mutant blocks Na⁺/K⁺-ATPase β1 trafficking to the cell surface in stria vascularis, collapsing the endocochlear potential, provided the first molecular mechanism for WFS1-associated sensorineural hearing loss.

    Evidence Wfs1E864K knock-in mouse; endocochlear potential electrophysiology; Na⁺/K⁺-ATPase β1 immunolocalization; auditory threshold testing

    PMID:37386014

    Open questions at the time
    • Direct binding interface between WFS1 and Na⁺/K⁺-ATPase β1 not mapped
    • Whether ER retention of β1 is due to misfolding or specific WFS1-dependent trafficking unknown
  12. 2024 High

    Confirming in a knock-in mouse that WFS1-E864K reduces MAM contacts, ER-to-mitochondria Ca²⁺ transfer, and mitochondrial bioenergetics while deregulating autophagy/mitophagy consolidated the MAM-mitochondrial axis as a core disease mechanism.

    Evidence Human fibroblasts and murine neurons from WFS1E864K carriers; OCR, Ca²⁺ uptake, autophagy/mitophagy flux, EM of MAMs in knock-in mice

    PMID:38651637

    Open questions at the time
    • Causal hierarchy between Ca²⁺ transfer defect and mitophagy deregulation not established
    • Whether pharmacological MAM stabilization can rescue phenotypes untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The direct molecular activity of WFS1—whether it functions as a channel, transporter, scaffold, or enzyme—remains unknown, and no high-resolution structure has been determined to explain how it coordinates ER stress relief, granule acidification, MAM integrity, and membrane protein trafficking.
  • No enzymatic or transport activity has been biochemically reconstituted
  • No cryo-EM or crystal structure of WFS1 exists
  • Mechanistic integration of ER stress, Ca²⁺, MAM, and secretory granule phenotypes into a unified model is lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3
Localization
GO:0005783 endoplasmic reticulum 5 GO:0005634 nucleus 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-382551 Transport of small molecules 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 1
Partners
ATP1B1CISD2VDAC1

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 WFS1 encodes an ER-resident transmembrane glycoprotein whose mRNA and protein are induced by ER stress; WFS1 expression is regulated by IRE1 and PERK (central UPR regulators), and inactivation of WFS1 in beta-cells causes ER stress and beta-cell dysfunction, establishing WFS1 as a novel component of the unfolded protein response that maintains ER homeostasis in pancreatic beta-cells. WFS1 mRNA/protein induction measured under ER stress; siRNA knockdown of WFS1 in beta-cell lines; pharmacological inhibition of IRE1 and PERK; functional readouts of ER stress markers The Journal of biological chemistry High 16195229
2011 WFS1 protein localizes not only to the ER but also to secretory granules in pancreatic beta-cells; WFS1 deficiency reduces intragranular acidification by ~32%, impairs proinsulin processing (elevated circulating proinsulin), and reduces the density of secretory granules docked at the plasma membrane, linking WFS1 to granule acidification and priming for exocytosis. Immunofluorescence and electron microscopy for localization; acidotrophic dye (DAMP) fluorescence assay for intragranular pH; morphometric EM analysis of granule docking; proinsulin radioimmunoassay in Wfs1-null mice Human molecular genetics High 21199859
2017 A heterozygous dominant WFS1 mutation (p.N325_I328del) causes constitutive ER stress via ATF6α activation and reduces SERCA2b mRNA expression, leading to dysregulated ER/cytosolic Ca2+ homeostasis and cell apoptosis. Luciferase reporter assay for ER stress response element (GRP78/ATF6α promoter); NFAT reporter for cytosolic Ca2+ elevation; RT-PCR for SERCA2b expression; transfection of mutant vs. wild-type WFS1 in cell lines Pediatric diabetes Medium 28271591
2020 Dominant WFS1 mutants (p.His313Tyr, p.Trp314Arg, p.Asp325_Ile328del, p.Glu809Lys, p.Glu864Lys) exert a dominant-negative effect on wild-type WFS1, elevating ER stress and CHOP mRNA; treatment with 4-phenylbutyrate (PBA) or valproate (VPA) reduces mutant-induced ER stress and cell apoptosis. Luciferase assay of ER stress response element; quantitative RT-PCR of CHOP; pharmacological rescue with PBA/VPA in transfected cells Journal of endocrinological investigation Medium 32219690
2021 WFS1 and CISD2 both localize at the ER and form complexes with Ca2+ transporters and Ca2+ channels, modulating ER Ca2+ signaling; their convergent role in Ca2+ homeostasis underlies the similar disease phenotypes seen with loss-of-function mutations in either gene. Review of co-immunoprecipitation and functional Ca2+ signaling studies; protein complex analysis compiled from the literature Science signaling Medium 34582248
2023 WFS1 interacts with VDAC1 at mitochondria-associated ER membranes (MAMs); loss of the WFS1-VDAC1 interaction in Wolfram syndrome hiPSC-derived neurons compromises mitochondrial function (bioenergetics, Ca2+ uptake, mitochondrial network), and restoring WFS1 levels reinstates this interaction and improves neuronal viability. Co-immunoprecipitation of WFS1 and VDAC1; hiPSC-derived neurons from WS patients; WFS1 overexpression rescue; mitochondrial bioenergetics assay (oxygen consumption rate); Ca2+ uptake assay; confocal imaging of MAM contacts Stem cell reports High 37163979
2024 The Wolfram-like syndrome mutant WFS1E864K reduces ER-to-mitochondria Ca2+ transfer, decreases mitochondrial bioenergetics and Ca2+ uptake, deregulates mitochondrial quality control (autophagy/mitophagy), and is associated with a decrease in MAM number in Wfs1 knock-in mice. Human fibroblasts and murine neuronal cultures from WFS1E864K carriers; mitochondrial bioenergetics (OCR); Ca2+ uptake measurements; autophagy/mitophagy flux assays; electron microscopy of MAM contacts in knock-in mice Autophagy High 38651637
2023 WFS1 is required for maintenance of the endocochlear potential; in Wfs1E864K knock-in mice, the mutant protein prevents trafficking of the Na+/K+-ATPase β1 subunit to the cell surface in stria vascularis, causing collapse of the endocochlear potential and profound hearing loss. Wfs1E864K knock-in mouse model; electrophysiology (endocochlear potential measurement); immunolocalization of Na+/K+-ATPase β1 in stria vascularis; histology of stria vascularis and neurosensory epithelium; auditory threshold testing Cell death & disease High 37386014
2009 WFS1 protein is expressed in pancreatic beta-cells and is normally up-regulated during insulin secretion; Wfs1-deficient mice on an obese/insulin-resistant background develop selective beta-cell apoptosis and severe insulin-deficient diabetes associated with markedly dilated ER and elevated ER stress markers (BiP/GRP78 and phospho-eIF2α), demonstrating that increased insulin demand accelerates ER stress-mediated apoptosis in Wfs1-null beta-cells. Wfs1-/- mice crossed with agouti lethal yellow (Ay/a) obese mice; immunoblot for BiP/GRP78 and p-eIF2α; TUNEL apoptosis assay; electron microscopy of ER morphology; pioglitazone pharmacological rescue Diabetologia High 19190890
2022 WFS1 deficiency enhances expression of pro-inflammatory cytokines and chemokines in pancreatic beta-cells; PERK and IRE1α pathways mediate high-glucose-induced inflammation in a WFS1-deficient beta-cell model; Wfs1 whole-body knockout mice show M1-macrophage infiltration and hypervascularization of pancreatic islets. WFS1 siRNA knockdown in beta-cell line; cytokine/chemokine gene expression by RT-PCR; pharmacological inhibition of PERK and IRE1α; immunohistochemistry of pancreatic islets from Wfs1 KO mice Frontiers in endocrinology Medium 35399956
2021 WFS1 silencing in PBMCs induces a pronounced pro-inflammatory cytokine profile (TNF-α, IL-1β, IL-6) without constitutive ER stress activation, and WFS1 deficiency is associated with a dominance of Th17 over regulatory T cells, revealing an anti-inflammatory role of WFS1 in immune cells. WFS1 siRNA knockdown in PBMCs from healthy donors; cytokine measurement by ELISA; T-cell subset analysis by flow cytometry; comparison with PBMCs from Wolfram syndrome patient Human molecular genetics Medium 33693650
2003 WFS1/wolframin is an 890-amino acid glycoprotein predominantly localized to the endoplasmic reticulum; immunohistochemistry with an ER marker confirms its ER localization in mouse inner ear cells, with expression pattern resembling cells containing canalicular reticulum, suggesting a role in ion homeostasis. Immunohistochemistry and in situ hybridization in mouse inner ear; double immunostaining with ER marker; developmental stage comparison Histochemistry and cell biology Medium 12649740
2008 Wfs1 protein is robustly enriched in the central extended amygdala and ventral striatum in the mouse brain, with prominent expression in the hippocampal CA1 region, hypothalamic magnocellular neurosecretory system, and central auditory pathway; this neuroanatomical distribution links Wfs1 loss-of-function to neurological and psychiatric symptoms of Wolfram syndrome. Immunohistochemistry in wild-type mice and X-Gal staining of Wfs1 KO mice with lacZ reporter insertion; brain-region mapping The Journal of comparative neurology Medium 18551525
2013 Wfs1 deficiency in mice results in impaired dopaminergic system function: blunted amphetamine-induced hyperlocomotion, reduced striatal dopamine levels after amphetamine, and significantly reduced dopamine transporter (Dat) mRNA expression in the midbrain. Wfs1 KO mouse behavioral testing (open field); tissue dopamine and metabolite measurement; quantitative RT-PCR for Dat mRNA; pharmacological challenge with amphetamine and apomorphine Behavioural brain research Medium 23396150
2018 Neuronal knockdown of wfs1 (Drosophila ortholog) causes age-dependent behavioral deficits and neurodegeneration; wfs1 knockdown increases susceptibility to oxidative stress-, excitotoxicity-, and tauopathy-induced neurodegeneration; glutamate release inhibitor riluzole suppresses premature death induced by wfs1 knockdown in neurons and glia. Drosophila wfs1 RNAi knockdown in neurons/glia; behavioral assays; survival analysis; pharmacological rescue with riluzole; genetic epistasis with excitotoxicity/oxidative stress models PLoS genetics Medium 29357349
2014 Wfs1-deficient mice show progressive visual evoked potential alterations (decreased amplitude, increased latency) and ER stress activation (elevated BiP, PDI, IRE1α) in retinas, indicating functional alteration of the optic pathway associated with ER stress in the absence of WFS1. Electroretinogram and visual evoked potentials in Wfs1-/- mice (3-12 months); immunolabeling of ER stress markers (BiP, PDI, IRE1α) in retinal sections; RGC quantification; electron microscopy of optic nerve PloS one Medium 24823368
2024 In the basolateral amygdala, WFS1-expressing glutamatergic neurons (BLAWFS1 neurons) have their excitability modulated by adjacent astrocytes via D-serine acting on NMDA receptors; optogenetic activation of BLA astrocytes restores BLAWFS1 neuron firing and improves risk-assessment behavior in a schizophrenia mouse model. Single-nucleus RNA sequencing; patch-clamp electrophysiology coupled with real-time RT-PCR; optogenetic activation of BLA astrocytes; NMDA receptor pharmacology; behavioral testing in DISC1-N transgenic mice Neuron Medium 38642554
2011 Wfs1 KO male mice have reduced fertility due to decreased spermatogonia and Sertoli cell numbers and altered sperm morphology, without changes in serum testosterone or FSH, indicating a cell-autonomous role of WFS1 in testicular cell survival. Wfs1 KO mouse breeding studies; sperm motility and morphology analysis; testis histology and cell counting; serum testosterone and FSH measurement Reproductive biology and endocrinology Low 19664290

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet (London, England) 475 7490992
2005 WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells. The Journal of biological chemistry 295 16195229
2007 Common variants in WFS1 confer risk of type 2 diabetes. Nature genetics 277 17603484
1997 Wolfram (DIDMOAD) syndrome. Journal of medical genetics 200 9350817
2001 Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss. Human molecular genetics 187 11709537
1999 Clinical and molecular genetic analysis of 19 Wolfram syndrome kindreds demonstrating a wide spectrum of mutations in WFS1. American journal of human genetics 164 10521293
2003 Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease. Human mutation 141 12955714
2001 WFS1/wolframin mutations, Wolfram syndrome, and associated diseases. Human mutation 125 11317350
2001 Non-syndromic progressive hearing loss DFNA38 is caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1. Human molecular genetics 114 11709538
2010 Wolfram syndrome and WFS1 gene. Clinical genetics 112 20738327
1997 Wolfram (DIDMOAD) syndrome and Leber hereditary optic neuropathy (LHON) are associated with distinct mitochondrial DNA haplotypes. Genomics 85 9027481
2007 Replication of the association between variants in WFS1 and risk of type 2 diabetes in European populations. Diabetologia 84 18040659
2003 The WFS1 gene, responsible for low frequency sensorineural hearing loss and Wolfram syndrome, is expressed in a variety of inner ear cells. Histochemistry and cell biology 82 12649740
2008 Distribution of Wfs1 protein in the central nervous system of the mouse and its relation to clinical symptoms of the Wolfram syndrome. The Journal of comparative neurology 75 18551525
2005 Mutation analysis of the WFS1 gene in seven Danish Wolfram syndrome families; four new mutations identified. European journal of human genetics : EJHG 75 16151413
2002 Association studies of genetic variation in the WFS1 gene and type 2 diabetes in U.K. populations. Diabetes 73 11916957
2002 Mutations in the WFS1 gene that cause low-frequency sensorineural hearing loss are small non-inactivating mutations. Human genetics 67 12073007
2016 Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity. Clinical cancer research : an official journal of the American Association for Cancer Research 66 28039263
2009 Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice. Diabetologia 66 19190890
2007 Identification of novel mutations in WFS1 and genotype-phenotype correlation in Wolfram syndrome. American journal of medical genetics. Part A 63 17568405
2001 Presence of a major WFS1 mutation in Spanish Wolfram syndrome pedigrees. Molecular genetics and metabolism 61 11161832
2014 Wolfram syndrome in the Japanese population; molecular analysis of WFS1 gene and characterization of clinical features. PloS one 56 25211237
2011 Wolfram syndrome 1 gene (WFS1) product localizes to secretory granules and determines granule acidification in pancreatic beta-cells. Human molecular genetics 55 21199859
2007 Mutations in the WFS1 gene are a frequent cause of autosomal dominant nonsyndromic low-frequency hearing loss in Japanese. Journal of human genetics 54 17492394
2007 Testing of diabetes-associated WFS1 polymorphisms in the Diabetes Prevention Program. Diabetologia 53 18060660
2010 Autosomal dominant optic neuropathy and sensorineual hearing loss associated with a novel mutation of WFS1. Molecular vision 49 20069065
2013 Wolfram gene (WFS1) mutation causes autosomal dominant congenital nuclear cataract in humans. European journal of human genetics : EJHG 48 23531866
2017 Wfs1- deficient rats develop primary symptoms of Wolfram syndrome: insulin-dependent diabetes, optic nerve atrophy and medullary degeneration. Scientific reports 47 28860598
2005 Wolfram syndrome in French population: characterization of novel mutations and polymorphisms in the WFS1 gene. Human mutation 46 15605410
2003 Wolfram syndrome and suicide: Evidence for a role of WFS1 in suicidal and impulsive behavior. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 45 12707947
2003 Wolfram (DIDMOAD) syndrome: a multidisciplinary clinical study in nine Turkish patients and review of the literature. Acta paediatrica (Oslo, Norway : 1992) 44 12650300
2016 WFS1 in Optic Neuropathies: Mutation Findings in Nonsyndromic Optic Atrophy and Assessment of Clinical Severity. Ophthalmology 43 27395765
2014 Mutation update and uncommon phenotypes in a French cohort of 96 patients with WFS1-related disorders. Clinical genetics 42 24890733
2018 Identification of a missense variant in the WFS1 gene that causes a mild form of Wolfram syndrome and is associated with risk for type 2 diabetes in Ashkenazi Jewish individuals. Diabetologia 41 30014265
2000 Missense variations of the gene responsible for Wolfram syndrome (WFS1/wolframin) in Japanese: possible contribution of the Arg456His mutation to type 1 diabetes as a nonautoimmune genetic basis. Biochemical and biophysical research communications 41 10679252
2003 Molecular detection of novel WFS1 mutations in patients with Wolfram syndrome by a DHPLC-based assay. Human mutation 40 12754709
2001 Identification of novel WFS1 mutations in Italian children with Wolfram syndrome. Human mutation 40 11295831
2003 Molecular characterization of WFS1 in patients with Wolfram syndrome. The Journal of molecular diagnostics : JMD 39 12707373
2004 Polymorphisms in wolframin (WFS1) gene are possibly related to increased risk for mood disorders. The international journal of neuropsychopharmacology 38 15473915
2018 Knockdown of wfs1, a fly homolog of Wolfram syndrome 1, in the nervous system increases susceptibility to age- and stress-induced neuronal dysfunction and degeneration in Drosophila. PLoS genetics 35 29357349
2008 Identification of novel mutations of the WFS1 gene in Brazilian patients with Wolfram syndrome. European journal of endocrinology 35 19042979
1994 Mitochondrial mutation commonly associated with Leber's hereditary optic neuropathy observed in a patient with Wolfram syndrome (DIDMOAD). Journal of medical genetics 35 8071960
2018 WFS1 mutation screening in a large series of Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis. PloS one 34 29529044
1999 A gene for autosomal dominant hearing impairment (DFNA14) maps to a region on chromosome 4p16.3 that does not overlap the DFNA6 locus. Journal of medical genetics 33 10424813
2014 Impairment of visual function and retinal ER stress activation in Wfs1-deficient mice. PloS one 32 24823368
2009 Expression of the diabetes risk gene wolframin (WFS1) in the human retina. Experimental eye research 32 19523951
2003 Progression of low-frequency sensorineural hearing loss (DFNA6/14-WFS1). Archives of otolaryngology--head & neck surgery 31 12707188
2020 Function of WFS1 and WFS2 in the Central Nervous System: Implications for Wolfram Syndrome and Alzheimer's disease. Neuroscience and biobehavioral reviews 30 32949681
2011 Presentation and clinical course of Wolfram (DIDMOAD) syndrome from North India. Diabetic medicine : a journal of the British Diabetic Association 30 21726277
2017 A novel heterozygous mutation of the WFS1 gene leading to constitutive endoplasmic reticulum stress is the cause of Wolfram syndrome. Pediatric diabetes 29 28271591
2014 Identification of a novel missense mutation in the WFS1 gene as a cause of autosomal dominant nonsyndromic sensorineural hearing loss in all-frequencies. American journal of medical genetics. Part A 28 25250959
2002 WFS1 mutations in Spanish patients with diabetes mellitus and deafness. European journal of human genetics : EJHG 28 12107816
1982 The syndrome of diabetes insipidus, diabetes mellitus, optic atrophy, deafness, and other abnormalities (DIDMOAD-syndrome). Two affected sibs and a short review of the literature (98 cases). Klinische Wochenschrift 28 7045512
2011 Wfs1 mutation makes mice sensitive to insulin-like effect of acute valproic acid and resistant to streptozocin. Journal of physiology and biochemistry 27 21461749
2009 Male mice with deleted Wolframin (Wfs1) gene have reduced fertility. Reproductive biology and endocrinology : RB&E 27 19664290
2021 Uniting the divergent Wolfram syndrome-linked proteins WFS1 and CISD2 as modulators of Ca2+ signaling. Science signaling 26 34582248
1999 Autosomal dominant non-syndromal low-frequency sensorineural hearing impairment linked to chromosome 4p16 (DFNA14): statistical analysis of hearing threshold in relation to age and evaluation of vestibulo-ocular functions. Audiology : official organ of the International Society of Audiology 26 10437687
2023 Genomics of Wolfram Syndrome 1 (WFS1). Biomolecules 25 37759745
2010 Decreased insulin secretion and increased risk of type 2 diabetes associated with allelic variations of the WFS1 gene: the Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study. Diabetologia 25 21127832
2002 Confirmation of genetic homogeneity of nonsyndromic low-frequency sensorineural hearing loss by linkage analysis and a DFNA6/14 mutation in a Japanese family. Journal of human genetics 25 12181639
2022 Loss of Function of WFS1 Causes ER Stress-Mediated Inflammation in Pancreatic Beta-Cells. Frontiers in endocrinology 24 35399956
2021 Novel mutations in the WFS1 gene are associated with Wolfram syndrome and systemic inflammation. Human molecular genetics 24 33693650
2006 Wolfram/DIDMOAD syndrome, a heterogenic and molecularly complex neurodegenerative disease. Pediatric endocrinology reviews : PER 24 16639390
2013 Silencing of the WFS1 gene in HEK cells induces pathways related to neurodegeneration and mitochondrial damage. Physiological genomics 22 23321269
2003 No association of mutations and mRNA expression of WFS1/wolframin with bipolar disorder in humans. Neuroscience letters 22 12565131
2016 Expression pattern of wolframin, the WFS1 (Wolfram syndrome-1 gene) product, in common marmoset (Callithrix jacchus) cochlea. Neuroreport 21 27341211
2011 Identification of two novel missense WFS1 mutations, H696Y and R703H, in patients with non-syndromic low-frequency sensorineural hearing loss. Journal of genetics and genomics = Yi chuan xue bao 21 21356526
2023 Genotype and clinical characteristics of patients with Wolfram syndrome and WFS1-related disorders. Frontiers in genetics 20 37415600
2009 Wolfram syndrome 1 (Wfs1) mRNA expression in the normal mouse brain during postnatal development. Neuroscience research 20 19428703
2023 Delineating Wolfram-like syndrome: A systematic review and discussion of the WFS1-associated disease spectrum. Survey of ophthalmology 19 36764396
2023 Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome. Stem cell reports 19 37163979
2013 Evidence for impaired function of dopaminergic system in Wfs1-deficient mice. Behavioural brain research 19 23396150
2016 RNA-sequencing of WFS1-deficient pancreatic islets. Physiological reports 18 27053292
2015 Phenotype Prediction of Pathogenic Nonsynonymous Single Nucleotide Polymorphisms in WFS1. Scientific reports 18 26435059
2024 The Wolfram-like variant WFS1E864K destabilizes MAM and compromises autophagy and mitophagy in human and mice. Autophagy 17 38651637
2022 Propionigenium and Vibrio species identified as possible component causes of shrimp white feces syndrome (WFS) associated with the microsporidian Enterocytozoon hepatopenaei. Journal of invertebrate pathology 17 35659607
2010 Additional heterozygous 2507A>C mutation of WFS1 in progressive hearing loss at lower frequencies. The Laryngoscope 17 19877185
2008 Autoimmune disease in a DFNA6/14/38 family carrying a novel missense mutation in WFS1. American journal of medical genetics. Part A 17 18688868
2007 A novel mutation in the WFS1 gene identified in a Taiwanese family with low-frequency hearing impairment. BMC medical genetics 17 17517145
2008 A novel WFS1 mutation in a family with dominant low frequency sensorineural hearing loss with normal VEMP and EcochG findings. BMC medical genetics 16 18518985
2003 Identification of a novel mutation in WFS1 in a family affected by low-frequency hearing impairment. Mutation research 16 12650912
1997 Analysis of the mitochondrial DNA from patients with Wolfram (DIDMOAD) syndrome. Molecular and cellular biochemistry 16 9309689
2023 Mutation analysis of pathogenic non-synonymous single nucleotide polymorphisms (nsSNPs) in WFS1 gene through computational approaches. Scientific reports 15 37185285
2012 Association of rs734312 and rs10010131 polymorphisms in WFS1 gene with type 2 diabetes mellitus: a meta-analysis. Endocrine journal 15 23257691
2011 Rapidly progressive renal disease as part of Wolfram syndrome in a large inbred Turkish family due to a novel WFS1 mutation (p.Leu511Pro). European journal of medical genetics 15 21968327
2004 Genetic variations in the WFS1 gene in Japanese with type 2 diabetes and bipolar disorder. Molecular genetics and metabolism 15 15234338
2020 Effect of 4-phenylbutyrate and valproate on dominant mutations of WFS1 gene in Wolfram syndrome. Journal of endocrinological investigation 14 32219690
2003 The WFS1 (Wolfram syndrome 1) is not a major susceptibility gene for the development of psychiatric disorders. Psychiatric genetics 14 12605098
2022 AudioGene: refining the natural history of KCNQ4, GSDME, WFS1, and COCH-associated hearing loss. Human genetics 13 35038006
2015 Identification of unsuspected Wolfram syndrome cases through clinical assessment and WFS1 gene screening in type 1 diabetes mellitus patients. Gene 13 25895475
2015 Micro-RNA Binding Site Polymorphisms in the WFS1 Gene Are Risk Factors of Diabetes Mellitus. PloS one 13 26426397
2014 WFS1 and non-syndromic low-frequency sensorineural hearing loss: a novel mutation in a Portuguese case. Gene 13 24462758
2002 Autosomal dominant low-frequency hearing impairment (DFNA6/14): a clinical and genetic family study. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 13 12438850
2024 Astrocyte-mediated regulation of BLAWFS1 neurons alleviates risk-assessment deficits in DISC1-N mice. Neuron 12 38642554
2023 Wfs1E864K knock-in mice illuminate the fundamental role of Wfs1 in endocochlear potential production. Cell death & disease 12 37386014
2021 A mutant wfs1 zebrafish model of Wolfram syndrome manifesting visual dysfunction and developmental delay. Scientific reports 12 34650143
2020 Recurrent de novo WFS1 pathogenic variants in Chinese sporadic patients with nonsyndromic sensorineural hearing loss. Molecular genetics & genomic medicine 12 32567228
2017 Metabolomics of the Wolfram Syndrome 1 Gene (Wfs1) Deficient Mice. Omics : a journal of integrative biology 12 29257731
2023 The genetic and clinical characteristics of WFS1 related diabetes in Chinese early onset type 2 diabetes. Scientific reports 11 37277527
2022 BioExcel Building Blocks Workflows (BioBB-Wfs), an integrated web-based platform for biomolecular simulations. Nucleic acids research 11 35639735