GeneBe

WFS1

protein-coding

wolframin ER transmembrane glycoprotein

Gene 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]

Previous symbols:
  • DFNA6
  • DFNA14
  • DFNA38

MANE transcript

NM_006005.3

Inheritance

AD, AR

ClinVar variants

P:281U:1066B:615

Top phenotype

Wolfram syndrome 1

gnomAD constraint

pLI —, LoF o/e 1.62

Max pathogenic AF

—

Genomic locus

chr4:6,269,849-6,303,265

External References & Databases

Ensembl (ENSG00000109501)NCBI Gene (7466)OMIM (606201)HGNC:12762GenCCUniProt (O76024)AlphaFoldClinVar (WFS1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~33.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

early-onset nuclear cataractSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020376

Submitter: Orphanet

Wolfram-like syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013673

Submitter: Genomics England PanelApp

Wolfram syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009101

Submitter: Genomics England PanelApp

Wolfram-like syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013673

Submitter: Ambry Genetics

Wolfram-like syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013673

Submitter: G2P

autosomal dominant nonsyndromic hearing loss 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010963

Submitter: Labcorp Genetics (formerly Invitae)

type 2 diabetes mellitusLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0005148

Submitter: Labcorp Genetics (formerly Invitae)

Wolfram syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009101

Submitter: Labcorp Genetics (formerly Invitae)

Wolfram-like syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013673

Submitter: Labcorp Genetics (formerly Invitae)

Wolfram syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018105

Submitter: ClinGen

The WFS1 gene has been associated with autosomal recessive Wolfram syndrome using the ClinGen Clinical Validity Framework as of 7/24/17. This association was made using case-level data. For the purpose of this curation, 9​ variants (missense, in-frame del, nonsense, frameshift) have been reported in humans. Association is seen in at least 7 probands in 4 publications (12754709, 16151413, 21446023, 21602428). Many more evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. A meta-analysis was performed by de Heredia et al. 2013, of published Wolfram syndrome cases from 1998 to 2013 (23429432). This gene-disease association is supported by a homozygous null WFS1 mouse model and relevant expression studies. Of note, this gene has been separately curated for its association with autosomal dominant disease. In summary, WFS1 is definitively associated with autosomal recessive Wolfram syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss​ Working Group on 4/17/18.

Wolfram-like syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013673

Submitter: Orphanet

Wolfram-like syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013673

Submitter: PanelApp Australia

cataract 41STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007287

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

autosomal dominant nonsyndromic hearing loss 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010963

Submitter: PanelApp Australia

Wolfram syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009101

Submitter: PanelApp Australia

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

The *WFS1* gene was first associated with autosomal dominant nonsyndromic hearing loss in 2001 (Young et al., PMID: 11709538). Of note, the *WFS1* gene has been implicated in autosomal recessive Wolfram syndrome and autosomal dominant Wolfram-like syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, they have been curated separately by this expert panel. The nonsyndromic hearing loss in individuals with heterozygous *WFS1* variants is progressive and low frequency which is different from the high frequency hearing loss seen in Wolfram syndrome patients. Generally non-inactivating variants that are mainly located in and around the C-terminal protein domain have been found in families with isolated hearing loss; thus, loss of function variants were not scored in this curation. At least 35 unique variants (missense and in-frame deletions/duplications) that have been reported in 43 probands in 15 publications are included in this curation (PMIDs: 11709538, 11709537, 12073007, 12181639, 17492394, 18688868, 24909696, 25250959, 28802351, 29529044, 33297549, 34222109, 34599366, 37041640, 36958120). More cases that are reported in the literature are not included in this curation, as definitive status was reached (PMID: 34599366). Variants in this gene segregated with disease in at least 60 family members in several families (PMIDs: 11709537, 12073007, 12181639, 25250959, 28802351). This gene-disease relationship is supported by expression data and a knockin mouse model with a variant present in human patients which recapitulated the deafness phenotype (PMIDs: 12649740, 27341211, 37386014). One study showed reduction in myelin in Wolfram patients compared to both healthy and diabetic controls (PMID: 26888576). This study was not scored since it is not specific to isolated hearing loss but disrupted myelination of auditory nerves is a plausible explanation for hearing loss. In summary, *WFS1* is definitively associated with autosomal dominant nonsyndromic hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Hearing Loss GCEP on the meeting date June 25th, 2024 (SOP Version 10).

Wolfram syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018105

Submitter: Orphanet

Wolfram-like syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013673

Submitter: G2P

Wolfram-like syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013673

Submitter: ClinGen

*WFS1* was first reported in relation to autosomal dominant Wolfram-like syndrome in 2006 (Eiberg et al.​, PMID: 16648378). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, AD Wolfram-like syndrome and AD Neonatal diabetes, congenital cataracts and sensorineural hearing loss were lumped together as there are no differences in molecular mechanism, inheritance pattern and phenotypic variability. AR Wolfram syndrome was split due to differences in inheritance pattern and molecular mechanism while AD nonsyndromic hearing loss was split due to differences in phenotypic variability. These split curations have been assessed separately by this expert panel. Biallelic *WFS1* variants in Wolfram syndrome patients are spread over the entire coding region and are typically inactivating, while non-inactivating heterozygous variants that are mainly located in and around the C-terminal protein domain have been found in families with Wolfram-like syndrome. At least eleven unique variants (10 missense, 1 inframe deletion) in this gene have been reported in 21 probands in 14 publications (PMIDs: 18544103, 20069065, 21538838, 27395765, 27217304, 28468959, 36330437, 34643356, 33075784, 33179441, 32700054, 37217489, 38296324, doi:10.1007/s13410-018-0674-6). The de novo variants were implicated with a more severe phenotype. Variants in this gene segregated with disease in 5 additional family members (PMID: 21538838). This gene-disease relationship is also supported by expression and functional alteration evidence (PMID: 27341211, 28468959). In summary, *WFS1* is definitively associated with autosomal dominant Wolfram-like syndrome. This gene-disease relationship was originally evaluated by the ClinGen Hearing Loss GCEP on 4/17/2018 as per SOP v6. It was reevaluated on 6/25/2024 using SOP v10. As a result of this reevaluation, this record underwent a lumping and splitting update and new case level and experimental evidence has been added, but the classification did not change (PMIDs: 28468959, 36330437, 34643356, 33075784, 33179441, 32700054, 32531870, 37217489, 38296324, doi:10.1007/s13410-018-0674-6).

Clinical Genomic Database (CGD)

Wolfram syndrome 1AR

Manifestation: Audiologic/Otolaryngologic; Endocrine; Neurologic; Ophthalmologic; Renal

Intervention: Audiologic/Otolaryngologic; Endocrine; Renal

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Recognition and interventions related to endocrine anomalies (eg, diabetes insipidus, diabetes mellitus) may be beneficial; Awareness of the possibility of renal anomalies (eg, hydronephrosis) may allow surveillance and management to potentially benefit renal/urologic function

Comments: A small proportion of individuals may have congenital deafness

Refs: 5956444; 8595423; 9817917; 10521293; 11709537; 11317350; 11709538; 12107816; 12181639; 15070927; 16151413; 17568405; 17492394; 18806274; 21823543; 21917145; 21446023; 22238590; 21968327; 22498363; 22226368; 23531866Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WFS1 variants in ClinVar

39 Conditions Cataloged
not providedTotal: 1792
Wolfram syndrome 1Total: 840
Autosomal dominant nonsyndromic hearing loss 6Total: 589
Wolfram-like syndromeTotal: 492
Type 2 diabetes mellitusTotal: 481
Cataract 41Total: 472
not specifiedTotal: 464
WFS1-related disorderTotal: 366

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006005.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
17
clinvar
501
clinvar
18
clinvar
 536
missense
20
clinvar
116
clinvar
1044
clinvar
83
clinvar
13
clinvar
 1276
nonsense
27
clinvar
32
clinvar
2
clinvar
 61
start loss
0
frameshift
31
clinvar
42
clinvar
3
clinvar
 76
splice donor/acceptor (+/-2bp)
6
clinvar
7
clinvar
 13
Total841971066584311962

Highest pathogenic variant AF is 0.00034849514

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 52 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_006005.3RefSeqNP_005996.27MANE Select
ENST00000226760.5EnsemblENSP00000226760.17MANE Select
NM_001145853.1RefSeqNP_001139325.17Standard
ENST00000503569.5EnsemblENSP00000423337.17Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
wfs1bDanio rerio

Structure: pancreatic B cell

Quality: decreased area

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Protein processing in endoplasmic reticulum - Homo sapiens (human)
  • XBP1(S) activates chaperone genes
  • Post-translational protein phosphorylation
  • Post-translational protein modification
  • Metabolism of proteins

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • kidney development
  • renal water homeostasis
  • ER overload response
  • visual perception

Molecular Function

  • protein binding
  • calmodulin binding
  • ubiquitin protein ligase binding
  • activating transcription factor binding
  • calcium-dependent protein binding

Cellular Component

  • proteasome complex
  • endoplasmic reticulum
  • endoplasmic reticulum lumen
  • endoplasmic reticulum membrane
  • integral component of endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000226760
Coding exons
7
Length
33417
Individuals with no LoFs
125632
Homozygous LoFs
0
Heterozygous LoFs
116
Defined
125748
p
0.000461
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-4.718905731.550.00004105744
Missense (PolyPhen)302217.581.3882233
Synonymous-10.24762651.790.00002161822
Loss of Function-3.094729.01.620.00000136321

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000250.00025rare
Latino/Admixed American0.000570.00055rare
Ashkenazi Jewish00.0absent
East Asian0.00100.0010notable
Finnish0.000330.00032rare
European (Non-Finnish)0.000510.00049rare
South Asian0.000300.00029rare
Other0.000330.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Participates in the regulation of cellular Ca(2+) homeostasis, at least partly, by modulating the filling state of the endoplasmic reticulum Ca(2+) store. {ECO:0000269|PubMed:16989814}.;
Disease
DISEASE: Wolfram syndrome 1 (WFS1) [MIM:222300]: A rare disorder characterized by juvenile-onset insulin-dependent diabetes mellitus with optic atrophy. Other manifestations include diabetes insipidus, sensorineural deafness, dementia, psychiatric illnesses. {ECO:0000269|PubMed:10521293, ECO:0000269|PubMed:11161832, ECO:0000269|PubMed:11295831, ECO:0000269|PubMed:15605410, ECO:0000269|PubMed:21538838, ECO:0000269|PubMed:22226368, ECO:0000269|PubMed:9771706, ECO:0000269|PubMed:9817917}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal dominant, 6 (DFNA6) [MIM:600965]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA6 is a low-frequency hearing loss in which frequencies of 2000 Hz and below are predominantly affected. Many patients have tinnitus, but there are otherwise no associated features such as vertigo. Because high-frequency hearing is generally preserved, patients retain excellent understanding of speech, although presbycusis or noise exposure may cause high-frequency loss later in life. DFNA6 worsens over time without progressing to profound deafness. {ECO:0000269|PubMed:11709537, ECO:0000269|PubMed:11709538, ECO:0000269|PubMed:12181639, ECO:0000269|PubMed:17517145, ECO:0000269|PubMed:18518985, ECO:0000269|PubMed:18688868, ECO:0000269|PubMed:21356526, ECO:0000269|PubMed:24462758, ECO:0000269|PubMed:25388789}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Wolfram-like syndrome autosomal dominant (WFSL) [MIM:614296]: A disease characterized by the clinical triad of congenital progressive hearing impairment, diabetes mellitus, and optic atrophy. The hearing impairment, which is usually diagnosed in the first decade of life, is relatively constant and alters mainly low- and middle-frequency ranges. {ECO:0000269|PubMed:16648378, ECO:0000269|PubMed:20069065, ECO:0000269|PubMed:21538838}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cataract 41 (CTRCT41) [MIM:116400]: An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. {ECO:0000269|PubMed:23531866}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.110

Intolerance Scores

LoFtool
0.00682
RVIS EVS
-0.1
RVIS percentile EVS
45.69

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.881

Gene Damage Prediction

AllRecessiveDominant
MendelianHighHighHigh
Primary ImmunodeficiencyHighHighHigh
CancerHighHighHigh
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