Incidental Mutation '2107:Wfs1'

• ID: 146
• Institutional Source: Beutler Lab
• Gene Symbol: Wfs1
• Ensembl Gene: ENSMUSG00000039474
• Gene Name: wolframin ER transmembrane glycoprotein
• Synonyms: wolframin, Wolfram syndrome 1 homolog (human)
• Essential gene?: Possibly non essential (E-score: 0.416)
• Stock #: 2107 of strain triaka
• Status: Validated
• Chromosome: 5
• Chromosomal Location: 37123448-37146326 bp(-) (GRCm39)
• Type of Mutation: missense
• DNA Base Change (assembly): C to T at 37124617 bp (GRCm39)
• Zygosity: Heterozygous
• Amino Acid Change: Arginine to Histidine at position 758 (R758H)
• Ref Sequence: ENSEMBL: ENSMUSP00000048053
• Gene Model: predicted gene model for transcript(s): [ENSMUST00000043964] [ENSMUST00000166339]
• AlphaFold: P56695
• Predicted Effect: probably damaging; Transcript: ENSMUST00000043964; AA Change: R758H; PolyPhen 2 Score 0.996 (Sensitivity: 0.55; Specificity: 0.98)
• SMART Domains: Protein: ENSMUSP00000048053; Gene: ENSMUSG00000039474; AA Change: R758H

Domain	Start	End	E-Value	Type
low complexity region	6	23	N/A	INTRINSIC
low complexity region	50	67	N/A	INTRINSIC
Blast:SEL1	101	139	1e-8	BLAST
low complexity region	268	275	N/A	INTRINSIC
transmembrane domain	313	335	N/A	INTRINSIC
transmembrane domain	342	364	N/A	INTRINSIC
transmembrane domain	407	424	N/A	INTRINSIC
transmembrane domain	431	453	N/A	INTRINSIC
transmembrane domain	495	517	N/A	INTRINSIC
transmembrane domain	529	551	N/A	INTRINSIC
transmembrane domain	561	583	N/A	INTRINSIC
transmembrane domain	590	612	N/A	INTRINSIC
transmembrane domain	632	654	N/A	INTRINSIC
low complexity region	877	886	N/A	INTRINSIC

• Predicted Effect: probably benign; Transcript: ENSMUST00000166339; AA Change: R682H; PolyPhen 2 Score 0.002 (Sensitivity: 0.99; Specificity: 0.30)
• SMART Domains: Protein: ENSMUSP00000132404; Gene: ENSMUSG00000039474; AA Change: R682H

Domain	Start	End	E-Value	Type
low complexity region	6	23	N/A	INTRINSIC
low complexity region	50	67	N/A	INTRINSIC
Blast:SEL1	101	139	3e-8	BLAST
low complexity region	268	275	N/A	INTRINSIC
low complexity region	334	345	N/A	INTRINSIC
transmembrane domain	419	441	N/A	INTRINSIC
transmembrane domain	453	475	N/A	INTRINSIC
transmembrane domain	485	507	N/A	INTRINSIC
transmembrane domain	514	536	N/A	INTRINSIC
transmembrane domain	556	578	N/A	INTRINSIC
low complexity region	801	810	N/A	INTRINSIC

• Predicted Effect: probably benign; Transcript: ENSMUST00000167937
• SMART Domains: Protein: ENSMUSP00000125779; Gene: ENSMUSG00000039474

Domain	Start	End	E-Value	Type
Blast:SEL1	20	58	4e-9	BLAST

• Meta Mutation Damage Score: 0.2672
• Coding Region Coverage:
  • 1x: 86.3%
  • 3x: 63.7%
• Validation Efficiency: 80% (79/99)
• MGI Phenotype: FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] 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] ; PHENOTYPE: Mice homozygous for a null allele exhibit decreased pancreatic beta cells and impaired glucose tolerance. Mice homozygous for a knock-out allele exhibit impaired glucose tolerance, decreased body weight, and abnormal behavior associated with increased sensitivity to stress. [provided by MGI curators]
• Allele List at MGI:

  All alleles(5) : Targeted, knock-out(1) Targeted, other(3) Gene trapped(1)

• Posted On: 2010-03-19

Nature of Mutation

DNA sequencing using the SOLiD technique identified a G to A transition at position 2395 of the Wfs1 transcript in exon 8 of 8 total exons. The mutated nucleotide causes an arginine to histidine substitution at amino acid 758 of the encoded protein. The mutation has been confirmed by DNA sequencing using the Sanger method (Figure 1).

Protein Function and Prediction

The Wfs1 gene encodes an 890 amino acid protein known as Wolframin. Wolframin is a multi-pass endoplasmic reticulum (ER) membrane protein that participates in the regulation of cellular Ca²⁺ homeostasis, at least partly, by modulating the filling state of the endoplasmic reticulum Ca²⁺ store (Uniprot P56695). Mice homozygous for a null allele exhibit decreased numbers of pancreatic beta cells and impaired glucose tolerance. Mice homozygous for another knock-out allele exhibit impaired glucose tolerance, decreased body weight, and abnormal behavior associated with increased sensitivity to stress.

 

The R758H change is predicted to be possibly damaging by the PolyPhen program.