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FLASH GENE

Symbol

WFS1

contributors: mct - updated : 06-11-2018

HGNC name	Wolfram syndrome 1 (wolframin)
HGNC id	12762

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	ADCC5 congenital cataract, zonular central nuclear 5 DFNA14 neurosensory deafness 14 DFNA38 neurosensory deafness 38 DFNA6 neurosensory deafness 6 DIDMOAD Wolfram syndrome JOD juvenile-onset diabetes NDCCD neonatal/infancy-onset diabetes, congenital cataracts, and sensorineural deafness
Location	4p16.1      Physical location : 6.271.576 - 6.304.991
Synonym name	wolframin
Synonym symbol(s)	WM1, WFRS, WFS, FLJ51211

DNA

TYPE	functioning gene
STRUCTURE	33.42 kb     8 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter (CAAT box)
	Binding site   transcription factor
text structure	a conserved sequence (CGAGGCGCACCGTGATTGG) that is highly similar to the ER stress response element (ERSE), critical for the regulation of WFS1 by XBP1
	minimal promoter contains two DNA binding motifs (GC boxes) for the transcription factors Sp1/3/4 (transcription factors of the Sp family are important regulators of the WFS1 promoter)
	up-regulating control region containing three CCAAT box binding motifs

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

text	variants 1 and 2 encode the same protein

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_006005 8 - 3640 NP_005996 - 890 - 2011 21454619 NM_001145853 8 - 3636 NP_001139325 - 890 - 2011 21454619

EXPRESSION

Type

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Endocrine pancreas         Homo sapiens Nervous brain hindbrain cerebellum     Mus musculus   brain limbic system hippocampus Ammons horn   Mus musculus   brain diencephalon amygdala     Mus musculus Olfactory (smell) olfactory bulb         Mus musculus

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial secretory glandular endocrine

cells

System Cell Pubmed Species Stage Rna symbol Endocrine islet cell (alpha,beta...) Homo sapiens Nervous neuron

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

pregnancy

Text

placenta

IMPRINTING

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N and C terminal hydrophilic regions
	N-terminal cytoplasmic domain (AAs 2-285) binds to an equimolar unit of CALM1 in a Ca(2+)-dependent manner , and N-terminal domain is located in the cytoplasm, interacting with ATP6V1A
	a central hydrophobic core
	nine transmembrane domains
	five putative ASN glycosylation sites
	a sequence homolog to the prenyltransferase alpha subunit repeat structure
	C-terminal domain of the WFS1 protein is located in the ER lumen

secondary structure

endoglycosidase H sensitive

conjugated

GlycoP

HOMOLOGY

interspecies	homolog to murine Wfs1 (87.60 pc)
	homolog to rattus Wfs1 (86.92 pc)

Homologene

FAMILY

multispanning transmembrane family

CATEGORY

regulatory , storage , transport

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,lumen
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,cytoplasm,cytosolic,granule
	intracellular,nucleus
text	endoplasmic reticulum (ER) resident transmembrane protein
	additionally located in the secretory granules of pancreatic beta cells
	endoplasmic reticulum resident transmembrane protein

basic FUNCTION	playing a role in survival of islet beta-cells and neurons
	may be playing a role in membrane trafficking, protein processing, or regulation of ER calcium homeostasis
	playing an important role in both stimulus-secretion coupling for insulin exocytosis and maintenance of the beta-cell mass
	playing a regulatory rolesin ER-stress induced cell death
	having an important function in maintaining homeostasis of the endoplasmic reticulum (ER) in pancreatic beta-cells
	negatively regulate the cellular response to ER stress, thereby raising the possibility that dominant WFS1 mutations could alter WFS1 function by causing or enhancing a dysregulated ER stress response
	negatively regulates a key transcription factor involved in ER stress signaling, activating transcription factor 6alpha (ATF6), through the ubiquitin-proteasome pathway
	role in the negative regulation of ER stress signaling and in the pathogenesis of diseases involving chronic, unresolvable ER stress, such as pancreatic beta cell death in diabetes
	plays a key role in the negative regulation of a feedback loop of the ER stress network through the ubiquitin proteasome pathway
	localizes to secretory granules and determines granule acidification in pancreatic beta-cells
	endoplasmic reticulum (ER)-resident transmembrane protein that also localizes to secretory granules in pancreatic beta cells
	is involved in the stability of proton and sodium pump subunits, but does not protect ATP6V1A and ATP1B1 from proteasome-mediated degradation
	is thought to be a negative regulator of the ER stress response
	is necessary for the stability of the ATP6V1A subunit independently of its role in ER stress
	endoplasmic reticulum (ER)-resident transmembrane protein that is involved in the regulation of the unfolded protein response (UPR), intracellular ion homeostasis, cyclic adenosine monophosphate production and regulation of insulin biosynthesis and secretion
	importance of WFS1 in function and/or development of the eye lens

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

cellular trafficking transport

text	membrane trafficking

PATHWAY

metabolism

carbohydrate

signaling

sensory transduction/hearing , sensory transduction/vision

a component

INTERACTION

DNA

RNA

small molecule

protein	interacting with CALM1 (CALM1 binding is important for wolframin function and impairment of this interaction by mutation contributes to the pathology seen in Wolfram syndrome)
	specific degradation substrate of SMURF1 (interacts with WFS1 at the ER and promotes the ubiquitination and proteasomal degradation of WFS1)
	interaction between WFS1 and ATP6V1A (proton pump)
	role for WFS1 in the negative regulation of SERCA, providing further insights into the function of WFS1 in calcium homeostasis

cell & other

REGULATION

activated by	during insulin secretion
	XBP1

induced by

ER stress

Other

regulated by inositol requiring 1 and PKR-like ER kinase, central regulators of the unfolded protein response

ASSOCIATED DISORDERS

corresponding disease(s)

DIDMOAD , DFNA6 , DFNA14 , DFNA38 , JOD , ADCC5 , NDCCD

related resource

Hereditary Hearing Loss Homepage

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional somatic mutation     loss of function leading to instability and proteasomal degradation of wolframin constitutional       loss of function mediates a self-perpetuating cycle of cell death constitutional       loss of function influenced significantly the pathways related to tissue morphology, endocrine system development and function, molecular transport network

Susceptibility

to common type 2 diabetes to age-related hearing impairment (ARHI)

Variant & Polymorphism SNP	increasing the risk of type 2 diabetes
	heterozygous p.Tyr528His variant segregated completely with late-onset HI in which hearing deteriorated first at high frequencies and progressed to mid and low frequencies later in life

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

	Wfs1-null mouse exhibits progressive insulin deficiency causing diabetes
	mice with disrupted WFS1 exhibit progressive pancreatic beta cell loss, resulting from the activation of ER stress pathways, delayed cell cycle progression and apoptosis