Affinage

WFS1

Wolframin · UniProt O76024

Length
890 aa
Mass
100.3 kDa
Annotated
2026-06-11
100 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WFS1 (wolframin) is a multi-spanning, N-glycosylated endoplasmic reticulum transmembrane protein that maintains ER homeostasis and secretory function, and whose biallelic loss-of-function mutations cause Wolfram syndrome (PMID:9817917, PMID:11181571, PMID:12913071). It is an integral ER glycoprotein with nine transmembrane segments and N-cytoplasmic/C-luminal topology that assembles into ~400 kDa complexes, and its N-glycosylation is essential for protein stability (PMID:11181571, PMID:12913071, PMID:15522226). WFS1 functions as a vesicular cargo receptor for ER-to-Golgi transport, binding proinsulin and other secretory cargo through its luminal C-terminal segment while presenting a cytosolic N-terminal ER export signal recognized by the COPII subunit SEC24; its deficiency causes ER accumulation of proinsulin and impaired insulin secretion (PMID:34848728). Beyond trafficking, WFS1 is an integral component of the unfolded protein response, with its expression induced by ER stress through the IRE1, PERK, and ATF6β arms, and it restrains ER stress-driven apoptosis in pancreatic beta-cells (PMID:16195229, PMID:16571599, PMID:25447309). It supports secretory granule acidification and proinsulin processing by binding and stabilizing the V1A subunit of the vacuolar H+-ATPase (PMID:21199859, PMID:23035048), and it positively modulates ER Ca2+ uptake (PMID:16989814). At mitochondria-associated ER membranes WFS1 binds VDAC1 to sustain ER-to-mitochondria Ca2+ transfer and bioenergetics (PMID:37163979, PMID:38651637), and in the cochlear stria vascularis it is required for surface localization of the Na+/K+-ATPase β1 subunit and the endocochlear potential (PMID:37386014). WFS1 deficiency triggers chronic ER stress, progressive beta-cell loss, and pro-inflammatory responses, mechanistically linking the protein to the diabetes, deafness, and neurodegeneration of Wolfram syndrome (PMID:15056606, PMID:33693650, PMID:35399956).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 High

    Established that WFS1 is the causative gene for Wolfram syndrome, framing all subsequent mechanistic work as defining how a transmembrane protein causes a multisystem disorder.

    Evidence Positional cloning and mutation analysis in Wolfram syndrome patients

    PMID:9817917

    Open questions at the time
    • Did not define subcellular localization or molecular function
    • No biochemical activity assigned
  2. 2001 High

    Answered where wolframin acts by showing it is an ER-resident integral membrane glycoprotein, redirecting the field away from a mitochondrial-primary mechanism.

    Evidence Immunofluorescence, subcellular fractionation, and endoglycosidase H sensitivity in cultured cells

    PMID:11181571

    Open questions at the time
    • No molecular function or topology defined
    • Did not address later-described MAM/mitochondrial coupling
  3. 2003 High

    Defined the protein architecture, showing nine transmembrane segments, N-cyt/C-lum topology, oligomerization into ~400 kDa complexes, and that glycosylation and the R629W mutation control stability.

    Evidence Topology mapping, pulse-chase, and mutant expression in COS-7 cells

    PMID:12913071

    Open questions at the time
    • Function of the luminal/cytosolic termini not assigned
    • Composition of the higher-order complex unknown
  4. 2004 High

    Linked WFS1 to the ER stress response and beta-cell survival, showing ER stress induces WFS1 and that its loss causes progressive beta-cell apoptosis and impaired glucose-stimulated insulin secretion.

    Evidence Wfs1-null mice with glucose tolerance, insulin secretion, calcium imaging, and apoptosis assays; ER-stress-induced WFS1 with glycosylation-dependent stability in islets

    PMID:15056606 PMID:15522226

    Open questions at the time
    • Molecular target by which WFS1 limits apoptosis not identified
    • Mechanism of reduced calcium responses unresolved
  5. 2006 High

    Positioned WFS1 as a UPR component induced via IRE1/PERK whose loss causes beta-cell-specific chronic ER stress, with rescue by WFS1 or GRP78 re-expression and p21-driven cell-cycle/apoptosis defects.

    Evidence siRNA knockdown and WFS1/GRP78 rescue in beta-cell lines and islets with UPR markers, BrdU, and caspase-3 readouts

    PMID:16195229 PMID:16571599

    Open questions at the time
    • Direct biochemical role of WFS1 within the UPR not defined
    • Tissue specificity mechanism unexplained
  6. 2006 High

    Assigned a calcium-handling function, showing WFS1 levels positively set the rate of ER Ca2+ uptake and store-operated entry.

    Evidence Knockdown/overexpression in HEK293 cells with ER-targeted aequorin and Fura-2 imaging

    PMID:16989814

    Open questions at the time
    • Molecular mechanism of Ca2+ regulation (channel/pump partner) not identified
    • Relationship to UPR induction unclear
  7. 2011 High

    Extended WFS1 function to secretory granules, showing it is required for granular acidification, proinsulin processing, and granule docking.

    Evidence Immunofluorescence, EM, DAMP intragranular pH measurement, and morphometry in beta-cells

    PMID:21199859

    Open questions at the time
    • Molecular basis of acidification defect not yet defined
    • Did not identify the proton-pump partner
  8. 2012 High

    Provided a mechanism for acidification by showing WFS1 binds and stabilizes the vacuolar H+-ATPase V1A subunit via its N-terminal domain.

    Evidence Reciprocal endogenous Co-IP, domain mapping, and protein stability assays in HEK293 and neuroblastoma cells

    PMID:23035048

    Open questions at the time
    • Stoichiometry within the ~400 kDa complex unresolved
    • Direct vs indirect stabilization not distinguished
  9. 2014 Medium

    Identified ATF6β as a direct transcriptional inducer of WFS1, separating ATF6β from ATF6α in protecting beta-cells from ER-stress apoptosis.

    Evidence Microarray, promoter binding, and ATF6β knockdown with apoptosis assays in INS-1 cells

    PMID:25447309

    Open questions at the time
    • Single lab; reciprocal validation limited
    • Quantitative contribution of WFS1 to ATF6β protection not isolated
  10. 2021 High

    Defined WFS1's core molecular activity as a COPII cargo receptor, showing direct luminal binding of proinsulin and other cargo and an N-terminal ER export signal recognized by SEC24, with pathogenic luminal mutations disrupting cargo binding.

    Evidence Co-IP/pulldown, COPII vesicle reconstitution, SEC24 binding, domain mutagenesis, and trafficking assays in WFS1 KO cells

    PMID:34848728

    Open questions at the time
    • Full repertoire of cargo proteins not catalogued
    • Reconciliation with UPR and Ca2+ roles within one mechanism not established
  11. 2021 Medium

    Implicated WFS1 in immune regulation, showing its loss drives spontaneous pro-inflammatory cytokine production and Th17/Treg imbalance in immune cells.

    Evidence siRNA silencing in PBMCs with ELISA cytokine measurement and flow cytometry of T-cell subsets

    PMID:33693650

    Open questions at the time
    • Mechanism linking WFS1 loss to cytokine induction not defined
    • Single lab; no in vivo confirmation in this study
  12. 2023 High

    Established a MAM/mitochondrial role, showing WFS1 binds VDAC1 to maintain ER-mitochondria contacts and bioenergetics, with rescue restoring function.

    Evidence Co-IP, OCR, EM MAM quantification, and WFS1 overexpression rescue in Wolfram patient hiPSC-derived neurons

    PMID:37163979

    Open questions at the time
    • Direct vs indirect WFS1-VDAC1 interaction not resolved
    • Reconciliation with earlier non-mitochondrial localization not addressed
  13. 2023 High

    Explained Wolfram-associated deafness, showing WFS1 is required for Na+/K+-ATPase β1 surface localization in the stria vascularis and for the endocochlear potential.

    Evidence Wfs1E864K knock-in mice with EP measurement, ABR, and β1-subunit localization

    PMID:37386014

    Open questions at the time
    • Whether WFS1 directly traffics β1 via its cargo-receptor activity not tested
    • Single lab
  14. 2024 Medium

    Demonstrated that the dominant E864K (Wolfram-like) mutation reduces MAMs, ER-to-mitochondria Ca2+ transfer, bioenergetics, and autophagy/mitophagy flux, unifying dominant and recessive disease mechanisms.

    Evidence OCR, Ca2+ uptake, EM MAM quantification, and autophagy/mitophagy flux assays in patient fibroblasts and murine neurons

    PMID:38651637

    Open questions at the time
    • Causal order between Ca2+ defect and autophagy deregulation unclear
    • Single lab
  15. 2024 Medium

    Characterized WFS1-expressing neurons at the circuit level, defining basolateral amygdala WFS1 glutamatergic neurons whose excitability is gated by astrocyte-derived D-serine acting on NMDA receptors.

    Evidence Single-nucleus RNA-seq, patch-clamp, optogenetic astrocyte activation, and NMDA pharmacology in a DISC1-N mouse model

    PMID:38642554

    Open questions at the time
    • Cell-autonomous function of WFS1 in these neurons not tested
    • Relationship to Wolfram neurodegeneration not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How WFS1's distinct activities — COPII cargo receptor, UPR effector, ER Ca2+ regulator, V-ATPase stabilizer, MAM/VDAC1 tether, and Na+/K+-ATPase chaperone — derive from a single molecular mechanism, and which is primary in driving each tissue's pathology, remains unresolved.
  • No unifying biochemical model integrating cargo-receptor and ER-homeostasis functions
  • Tissue-specific primary defect (beta-cell vs cochlea vs neuron) not isolated
  • Structure of the native oligomeric complex unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2 GO:0038024 cargo receptor activity 1
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005739 mitochondrion 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-5653656 Vesicle-mediated transport 1
Partners
ATP1B1ATP6V1AGRP94HSPA5SEC24VDAC1
Complex memberships
COPII (via SEC24)WFS1 ~400 kDa membrane complexvacuolar H+-ATPase (V1A subunit)

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 WFS1 encodes a predicted transmembrane protein (wolframin) expressed in various tissues including brain and pancreas; loss-of-function mutations in both alleles cause Wolfram syndrome, establishing it as the disease gene on chromosome 4p16. Positional cloning, candidate gene screening, mutation analysis in Wolfram syndrome patients Human molecular genetics High 9817917
2001 WFS1 protein (wolframin) is an integral, endoglycosidase H-sensitive membrane glycoprotein that localizes primarily to the endoplasmic reticulum (ER); no co-localization with mitochondria was detected, arguing against a mitochondrial-mediated disorder mechanism. Immunofluorescence, subcellular fractionation, endoglycosidase H sensitivity assay, co-localization with ER marker in cultured cells Human molecular genetics High 11181571
2003 Wolframin contains nine transmembrane segments with N-cytoplasmic/C-luminal (N(cyt)/C(lum)) topology, assembles into higher molecular weight complexes (~400 kDa) in the membrane, and undergoes N-glycosylation (essential for biogenesis and stability) but lacks proteolytic processing. Missense mutation R629W causes instability and strongly reduced half-life of wolframin. Polyclonal antibody generation against both termini, topology mapping, pulse-chase experiments, COS-7 cell expression of mutant wolframin Human molecular genetics High 12913071
2004 ER stress upregulates WFS1 mRNA and protein in pancreatic islets; N-glycosylation at Asn-663 and Asn-748 is required for WFS1 protein stability — glycosylation-defective mutants show increased protein turnover. ER stress induction with thapsigargin/dithiothreitol/tunicamycin, site-directed mutagenesis, pulse-chase protein stability assays Biochemical and biophysical research communications High 15522226
2004 Wfs1-null mice develop progressive beta-cell loss and impaired insulin secretion in response to glucose, accompanied by reduced cellular calcium responses to secretagogues and increased apoptosis of beta-cells under ER stress conditions; alpha-cells which barely express WFS1 are preserved. Wfs1 gene disruption in mice, glucose tolerance tests, islet isolation and insulin secretion assays, calcium imaging, immunohistochemistry, DNA fragmentation apoptosis assay Human molecular genetics High 15056606
2005 WFS1 is a novel component of the unfolded protein response (UPR); WFS1 mRNA and protein are induced by ER stress through IRE1 and PERK pathways; WFS1 is upregulated during insulin secretion; inactivation of WFS1 in beta-cells causes ER stress and beta-cell dysfunction. ER stress induction, siRNA knockdown of WFS1 in beta-cells, UPR pathway reporter assays, IRE1/PERK pathway analysis The Journal of biological chemistry High 16195229
2006 WFS1-deficiency specifically activates the ER stress response in pancreatic beta-cells (elevated PERK phosphorylation, chaperone expression, active XBP1) but not in heart, skeletal muscle, or brown adipose tissue; this is reversed by re-expression of WFS1 or GRP78 overexpression. ER stress-induced increase in p21(CIP1) contributes to beta-cell loss through impaired cell cycle progression and increased caspase-3-mediated apoptosis. wfs1-deficient MIN6 clonal beta-cell lines, ER stress markers (PERK phosphorylation, XBP1, chaperone expression), BrdU incorporation, caspase-3 cleavage, WFS1 rescue experiments, GRP78 overexpression rescue Human molecular genetics High 16571599
2006 WFS1 protein positively modulates ER Ca2+ levels by increasing the rate of Ca2+ uptake into the ER; store-operated Ca2+ entry parallels WFS1 expression levels. WFS1 knockdown and overexpression in HEK293 cells, ER-targeted Ca2+-sensitive aequorin photoprotein, Fura-2 Ca2+ imaging FEBS letters High 16989814
2009 Valproate (a mood stabilizer) induces WFS1 mRNA expression, activates the WFS1 promoter, and dose-dependently enhances dissociation of WFS1 from its binding partner GRP94 (an ER stress-response protein), providing a molecular mechanism for valproate's action. WFS1 promoter luciferase assay, RT-PCR, co-immunoprecipitation of WFS1-GRP94 complex in cells treated with valproate PloS one Medium 19125190
2011 WFS1 localizes not only to the ER but also to secretory granules in pancreatic beta-cells; WFS1-deficiency causes a 32% reduction in granular acidification, impairs proinsulin processing, and reduces the density of secretory granules docked at the plasma membrane. Immunofluorescence, electron microscopy, acidotrophic agent (DAMP) fluorescence measurement of intragranular pH, morphometric electron microscopy analysis of docked granules, proinsulin/insulin measurement Human molecular genetics High 21199859
2012 WFS1 physically interacts with the V1A subunit of the vacuolar H+-ATPase (proton pump) via its N-terminal domain; WFS1 is required for V1A subunit stability (V1A is degraded more rapidly in WFS1-depleted cells), suggesting WFS1 functions in proton pump assembly in the ER and granular acidification. Co-immunoprecipitation in HEK293 cells and endogenous Co-IP in neuroblastoma cells, V1A domain mapping (N-terminal vs C-terminal of WFS1), protein stability assays, proteasomal inhibition, WFS1 stable/transient depletion in human neuroblastoma and NT2 cells Human molecular genetics High 23035048
2014 ATF6β (but not ATF6α) directly binds the WFS1 promoter and induces WFS1 gene and protein expression; ATF6β knockdown increases susceptibility to ER stress-induced apoptosis in beta-cells, partly through its failure to upregulate WFS1. Microarray after ATF6β/ATF6α overexpression, promoter binding assay (ChIP/binding assay), ATF6β knockdown in INS-1 cells, apoptosis assay Experimental cell research Medium 25447309
2021 WFS1 acts as a vesicular cargo receptor for ER-to-Golgi transport: it directly binds vesicular cargo proteins including proinsulin via its ER-luminal C-terminal segment, and its cytosolic N-terminal segment encodes an ER export signal recognized by COPII subunit SEC24. WFS1 deficiency causes abnormal ER accumulation of proinsulin, impairing proinsulin processing and insulin secretion. Pathogenic mutations in the C-terminal luminal region disrupt cargo binding. Co-IP/pulldown of WFS1 with proinsulin and other cargo proteins, COPII vesicle reconstitution, SEC24 binding assays, domain mutagenesis, WFS1 KO cells, proinsulin trafficking and processing assays Nature communications High 34848728
2021 WFS1 deficiency in peripheral blood mononuclear cells (PBMCs) and silencing via siRNA induces production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) without any exogenous stimulus, and promotes a Th17/Treg imbalance, indicating WFS1 regulates anti-inflammatory responses. WFS1 siRNA silencing in control PBMCs, cytokine measurement by ELISA, T-cell subset analysis (Th17/Treg) by flow cytometry in WS patient PBMCs Human molecular genetics Medium 33693650
2022 Loss of WFS1 function enhances pro-inflammatory cytokine and chemokine expression in pancreatic beta-cells; PERK and IRE1α pathways mediate high glucose-induced inflammation; WFS1 whole-body KO mice show M1-macrophage infiltration and hypervascularization of pancreatic islets. WFS1-deficient beta-cell model, qPCR for pro-inflammatory gene expression, Wfs1 KO mouse pancreatic islet histology, macrophage immunostaining Frontiers in endocrinology Medium 35399956
2023 WFS1 (Wfs1E864K knock-in) is required for endocochlear potential (EP) production in the stria vascularis; the WFS1E864K mutation prevents localization of the Na+/K+-ATPase β1 subunit to the cell surface, collapsing the EP and causing profound deafness. Wfs1E864K knock-in mouse model, EP measurement, stria vascularis histology, Na+/K+-ATPase β1 subunit localization by immunofluorescence, auditory brainstem response (ABR) Cell death & disease High 37386014
2023 WFS1 interacts with VDAC1 at mitochondria-associated ER membranes (MAMs); loss of WFS1-VDAC1 interaction in Wolfram syndrome patient-derived hiPSC neurons correlates with mitochondrial dysfunction, reduced MAMs, and impaired bioenergetics; restoring WFS1 levels reinstates VDAC1 interaction, increases MAMs, and improves mitochondrial function. Co-IP of WFS1 with VDAC1 in hiPSC-derived neurons, mitochondrial function assays (OCR), MAM quantification by electron microscopy, WFS1 overexpression rescue, pharmacological agents modulating mitochondrial function Stem cell reports High 37163979
2024 WFS1E864K (Wolfram-like syndrome mutation) decreases MAM number, reduces ER-to-mitochondria Ca2+ transfer, impairs mitochondrial bioenergetics and Ca2+ uptake, and deregulates autophagy/mitophagy flux in human fibroblasts and murine neuronal cultures; these are similar pathophysiological mechanisms to those in Wolfram syndrome. Human WLS fibroblasts and murine neuronal cultures, mitochondrial bioenergetics (OCR), Ca2+ uptake assays, MAM quantification by electron microscopy, autophagic flux assays (bafilomycin A1), mitophagy assays Autophagy Medium 38651637
2024 WFS1-expressing glutamatergic neurons in the basolateral amygdala (BLA) have their excitability modulated by adjacent astrocytes via D-serine acting on NMDA receptors; optogenetic activation of BLA astrocytes restores BLAWFS1 neuron firing and risk-assessment behavior in a DISC1-N mouse model. Single-nucleus RNA sequencing to identify BLAWFS1 neurons, patch-clamp electrophysiology, optogenetic astrocyte activation, NMDA receptor pharmacology, real-time RT-PCR Neuron Medium 38642554
2020 Dominant WFS1 mutants (p.His313Tyr, p.Trp314Arg, p.Asp325_Ile328del, p.Glu809Lys, p.Glu864Lys) exert a dominant-negative effect on wild-type WFS1, increasing ER stress (ERSE-luciferase) and CHOP mRNA; treatment with 4-phenylbutyrate or valproate reduces ER stress and cell apoptosis caused by these mutants. ERSE-luciferase ER stress reporter assay with dominant mutant co-expression, CHOP mRNA qPCR, cell viability assays, PBA/VPA pharmacological treatment Journal of endocrinological investigation Medium 32219690

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) 482 7490992
1998 Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein. Human molecular genetics 379 9817917
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 300 16195229
2001 WFS1 (Wolfram syndrome 1) gene product: predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain. Human molecular genetics 271 11181571
2004 Disruption of the WFS1 gene in mice causes progressive beta-cell loss and impaired stimulus-secretion coupling in insulin secretion. Human molecular genetics 217 15056606
2006 WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells. Human molecular genetics 207 16571599
1997 Wolfram (DIDMOAD) syndrome. Journal of medical genetics 202 9350817
2001 Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss. Human molecular genetics 188 11709537
2003 Wolfram syndrome: structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product. Human molecular genetics 164 12913071
2006 WFS1 protein modulates the free Ca(2+) concentration in the endoplasmic reticulum. FEBS letters 145 16989814
2003 Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease. Human mutation 142 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 113 20738327
2006 Autosomal dominant optic atrophy associated with hearing impairment and impaired glucose regulation caused by a missense mutation in the WFS1 gene. Journal of medical genetics 105 16648378
1997 Wolfram (DIDMOAD) syndrome and Leber hereditary optic neuropathy (LHON) are associated with distinct mitochondrial DNA haplotypes. Genomics 85 9027481
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
2005 Mutation analysis of the WFS1 gene in seven Danish Wolfram syndrome families; four new mutations identified. European journal of human genetics : EJHG 76 16151413
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
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
2008 Wfs1-deficient mice display impaired behavioural adaptation in stressful environment. Behavioural brain research 66 19041897
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
2009 Wfs1 gene deletion causes growth retardation in mice and interferes with the growth hormone pathway. Physiological genomics 57 19293327
2014 Wolfram syndrome in the Japanese population; molecular analysis of WFS1 gene and characterization of clinical features. PloS one 56 25211237
2009 Valproate, a mood stabilizer, induces WFS1 expression and modulates its interaction with ER stress protein GRP94. PloS one 56 19125190
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 54 18060660
2013 Wolfram gene (WFS1) mutation causes autosomal dominant congenital nuclear cataract in humans. European journal of human genetics : EJHG 49 23531866
2010 Autosomal dominant optic neuropathy and sensorineual hearing loss associated with a novel mutation of WFS1. Molecular vision 49 20069065
2012 Vacuolar-type H+-ATPase V1A subunit is a molecular partner of Wolfram syndrome 1 (WFS1) protein, which regulates its expression and stability. Human molecular genetics 47 23035048
2008 WFS1 mutations are frequent monogenic causes of juvenile-onset diabetes mellitus in Lebanon. Human molecular genetics 47 18806274
2005 Wolfram syndrome in French population: characterization of novel mutations and polymorphisms in the WFS1 gene. Human mutation 46 15605410
2016 WFS1 in Optic Neuropathies: Mutation Findings in Nonsyndromic Optic Atrophy and Assessment of Clinical Severity. Ophthalmology 45 27395765
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
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
2003 Molecular characterization of WFS1 in patients with Wolfram syndrome. The Journal of molecular diagnostics : JMD 39 12707373
2008 Autosomal dominant transmission of diabetes and congenital hearing impairment secondary to a missense mutation in the WFS1 gene. Diabetic medicine : a journal of the British Diabetic Association 37 18544103
2018 WFS1 mutation screening in a large series of Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis. PloS one 36 29529044
2021 WFS1 functions in ER export of vesicular cargo proteins in pancreatic β-cells. Nature communications 35 34848728
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
2014 Impairment of visual function and retinal ER stress activation in Wfs1-deficient mice. PloS one 33 24823368
2000 WFS1 gene mutation search in depressive patients: detection of five missense polymorphisms but no association with depression or bipolar affective disorder. Journal of affective disorders 33 10760554
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
2009 Expression of the diabetes risk gene wolframin (WFS1) in the human retina. Experimental eye research 32 19523951
2004 Endoplasmic reticulum stress and N-glycosylation modulate expression of WFS1 protein. Biochemical and biophysical research communications 32 15522226
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
2023 Genomics of Wolfram Syndrome 1 (WFS1). Biomolecules 29 37759745
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
2023 Genotype and clinical characteristics of patients with Wolfram syndrome and WFS1-related disorders. Frontiers in genetics 27 37415600
2021 Uniting the divergent Wolfram syndrome-linked proteins WFS1 and CISD2 as modulators of Ca2+ signaling. Science signaling 27 34582248
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
2022 Loss of Function of WFS1 Causes ER Stress-Mediated Inflammation in Pancreatic Beta-Cells. Frontiers in endocrinology 26 35399956
2014 ATF6β regulates the Wfs1 gene and has a cell survival role in the ER stress response in pancreatic β-cells. Experimental cell research 26 25447309
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
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
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 23 23321269
2023 Delineating Wolfram-like syndrome: A systematic review and discussion of the WFS1-associated disease spectrum. Survey of ophthalmology 22 36764396
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 Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome. Stem cell reports 20 37163979
2021 A novel mutation of WFS1 gene leading to increase ER stress and cell apoptosis is associated an autosomal dominant form of Wolfram syndrome type 1. BMC endocrine disorders 20 33879153
2009 Wolfram syndrome 1 (Wfs1) mRNA expression in the normal mouse brain during postnatal development. Neuroscience research 20 19428703
2007 WFS1 gene as a putative biomarker for development of post-traumatic syndrome in an animal model. Molecular psychiatry 20 17968352
2016 RNA-sequencing of WFS1-deficient pancreatic islets. Physiological reports 19 27053292
2014 Initiation and developmental dynamics of Wfs1 expression in the context of neural differentiation and ER stress in mouse forebrain. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 19 24694561
2013 Evidence for impaired function of dopaminergic system in Wfs1-deficient mice. Behavioural brain research 19 23396150
2024 The Wolfram-like variant WFS1E864K destabilizes MAM and compromises autophagy and mitophagy in human and mice. Autophagy 18 38651637
2015 Phenotype Prediction of Pathogenic Nonsynonymous Single Nucleotide Polymorphisms in WFS1. Scientific reports 18 26435059
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
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
2023 Mutation analysis of pathogenic non-synonymous single nucleotide polymorphisms (nsSNPs) in WFS1 gene through computational approaches. Scientific reports 16 37185285
2021 Wfs1 and Related Molecules as Key Candidate Genes in the Hippocampus of Depression. Frontiers in genetics 16 33552119
2004 Study of the WFS1 gene and mitochondrial DNA in Spanish Wolfram syndrome families. Clinical genetics 16 15151504
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
2012 Association of rs734312 and rs10010131 polymorphisms in WFS1 gene with type 2 diabetes mellitus: a meta-analysis. Endocrine journal 15 23257691
2004 Genetic variations in the WFS1 gene in Japanese with type 2 diabetes and bipolar disorder. Molecular genetics and metabolism 15 15234338
2024 Astrocyte-mediated regulation of BLAWFS1 neurons alleviates risk-assessment deficits in DISC1-N mice. Neuron 14 38642554
2020 Effect of 4-phenylbutyrate and valproate on dominant mutations of WFS1 gene in Wolfram syndrome. Journal of endocrinological investigation 14 32219690
2014 Wfs1-deficient animals have brain-region-specific changes of Na+, K+-ATPase activity and mRNA expression of α1 and β1 subunits. Journal of neuroscience research 14 25385034
2023 The genetic and clinical characteristics of WFS1 related diabetes in Chinese early onset type 2 diabetes. Scientific reports 13 37277527
2023 Wfs1E864K knock-in mice illuminate the fundamental role of Wfs1 in endocochlear potential production. Cell death & disease 13 37386014
2015 Micro-RNA Binding Site Polymorphisms in the WFS1 Gene Are Risk Factors of Diabetes Mellitus. PloS one 13 26426397
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

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