Reviewed April 2012
What is the official name of the WFS1 gene?
The official name of this gene is “Wolfram syndrome 1 (wolframin).”
WFS1 is the gene's official symbol. The WFS1 gene is also known by other names, listed below.
What is the normal function of the WFS1 gene?
The WFS1 gene provides instructions for producing a protein called wolframin that is thought to regulate the amount of calcium in cells. A proper calcium balance is important for many different cellular functions, including cell-to-cell communication, the tensing (contraction) of muscles, and protein processing. The wolframin protein is found in many different tissues, such as the pancreas, brain, heart, bones, muscles, lungs, liver, and kidneys.
Within cells, wolframin is located in the membrane of a structure called the endoplasmic reticulum. Among its many activities, the endoplasmic reticulum folds and modifies newly formed proteins so they have the correct 3-dimensional shape to function properly. The endoplasmic reticulum also helps transport proteins and other molecules to specific sites within the cell or to the cell surface. Wolframin is thought to play a role in protein folding and aid in the maintenance of endoplasmic reticulum function by regulating calcium levels. In the pancreas, wolframin may help fold a protein precursor of insulin (called proinsulin) into the mature hormone that controls blood glucose levels. In the inner ear, wolframin may help maintain the proper levels of calcium ions or other charged particles that are essential for hearing.
How are changes in the WFS1 gene related to health conditions?
- nonsyndromic deafness - caused by mutations in the WFS1 gene
More than 30 WFS1 gene mutations have been identified in individuals with a form of nonsyndromic deafness called DFNA6. People with this condition have hearing loss without related signs and symptoms affecting other parts of the body. Individuals with DFNA6 nonsyndromic deafness cannot hear low tones (low-frequency sounds), such as sounds from a tuba or the "m" in moon. Most WFS1 gene mutations change single protein building blocks (amino acids) used to make wolframin. WFS1 gene mutations probably result in a wolframin protein with an altered 3-dimensional shape, which could affect its function. It is thought that the loss of cells in the inner ear along with the disruption of the normal function of cells in the part of the brain responsible for hearing lead to hearing loss in affected individuals. Researchers also suggest that altered wolframin disturbs the balance of calcium in the inner ear, which interferes with the hearing process.
- Wolfram syndrome - caused by mutations in the WFS1 gene
At least 200 mutations in the WFS1 gene have been found to cause Wolfram syndrome. This condition is characterized by a lack of insulin leading to increased blood sugar (diabetes mellitus), a degeneration of nerves that carry information from the eyes to the brain (optic atrophy), and a number of other features involving the urinary tract, the brain, and hearing. Mutations in both copies of the WFS1 gene in each cell are necessary to cause Wolfram syndrome. Some mutations delete or insert pieces of DNA in the WFS1 gene, causing no functional wolframin to be made. Other mutations change single amino acids in the wolframin protein, reducing the protein's function. As a result, calcium levels within cells are not regulated and the endoplasmic reticulum does not function correctly.
When the endoplasmic reticulum cannot function, the cell triggers its own cell death (apoptosis). The death of cells in the pancreas, specifically cells that make insulin (beta cells), causes diabetes mellitus in people with Wolfram syndrome. The gradual loss of cells along the optic nerve eventually leads to blindness in affected individuals. The death of cells in other body systems likely causes the various signs and symptoms of Wolfram syndrome.
- other disorders - caused by mutations in the WFS1 gene
A few WFS1 gene mutations have been found to cause a condition known as Wolfram-like syndrome that is characterized by progressive hearing loss and optic atrophy leading to vision loss, typically beginning in adolescence. Some people with this condition also develop diabetes mellitus. These features are common in Wolfram syndrome, and Wolfram-like syndrome is considered a mild version of that condition.
Wolfram-like syndrome is caused by one WFS1 gene mutation in each cell. These mutations replace single amino acids in the wolframin protein, leading to a decrease in protein function. A reduction in functional wolframin protein leads to cell death, specifically affecting cells along the optic nerve, cells within the inner ear, and beta cells in the pancreas. A loss of these cells contributes to the features of Wolfram-like syndrome. The second copy of the WFS1 gene that does not have a mutation produces normal wolframin. The presence of some normal wolframin in each cell likely explains why Wolfram-like syndrome is less severe than Wolfram syndrome.
Where is the WFS1 gene located?
Cytogenetic Location: 4p16.1
Molecular Location on chromosome 4: base pairs 6,271,576 to 6,304,991
The WFS1 gene is located on the short (p) arm of chromosome 4 at position 16.1.
More precisely, the WFS1 gene is located from base pair 6,271,576 to base pair 6,304,991 on chromosome 4.
See How do geneticists indicate the location of a gene? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genelocation) in the Handbook.
Where can I find additional information about WFS1?
You and your healthcare professional may find the following resources about WFS1 helpful.
Educational resources - Information pages
- Florida State University: The Endoplasmic Reticulum (http://micro.magnet.fsu.edu/cells/endoplasmicreticulum/endoplasmicreticulum.html)
- The Cell, A Molecular Approach (2nd edition, 2000): The Endoplasmic Reticulum (http://www.ncbi.nlm.nih.gov/books/NBK9889/)
Gene Reviews - Clinical summary
- Gene Review: Hereditary Hearing Loss and Deafness (http://www.ncbi.nlm.nih.gov/books/NBK1434/)
- Gene Review: WFS1-Related Disorders (http://www.ncbi.nlm.nih.gov/books/NBK4144/)
Genetic Testing Registry - Repository of genetic test information
- GTR: Genetic tests for WFS1 (http://www.ncbi.nlm.nih.gov/gtr/tests/?term=7466%5Bgeneid%5D)
You may also be interested in these resources, which are designed for genetics professionals and researchers.
- PubMed - Recent literature (http://www.ncbi.nlm.nih.gov/pubmed?term=((WFS1%5BTIAB%5D)%20OR%20(Wolfram%20syndrome%201%5BTIAB%5D))%20AND%20((Genes%5BMH%5D)%20OR%20(Genetic%20Phenomena%5BMH%5D))%20AND%20english%5Bla%5D%20AND%20human%5Bmh%5D%20AND%20%22last%201800%20days%22%5Bdp%5D)
OMIM - Genetic disorder catalog
- WFS1 GENE (http://omim.org/entry/606201)
- WOLFRAM-LIKE SYNDROME, AUTOSOMAL DOMINANT (http://omim.org/entry/614296)
Research Resources - Tools for researchers
- GeneCards (http://www.genecards.org/cgi-bin/carddisp.pl?id_type=entrezgene&id=7466)
- Harvard Medical School Center for Hereditary Deafness (http://hearing.harvard.edu/db/genelist.htm)
- HUGO Gene Nomenclature Committee (http://www.genenames.org/data/hgnc_data.php?hgnc_id=12762)
- NCBI Gene (http://www.ncbi.nlm.nih.gov/gene/7466)
- The Hereditary Hearing Loss Homepage (http://hereditaryhearingloss.org/)
- WFS1 Gene Mutation and Polymorphism Database, Kresge Hearing Research Institute (http://www.khri.med.umich.edu/research/lesperance_lab/low_freq.php)
What other names do people use for the WFS1 gene or gene products?
See How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.
What glossary definitions help with understanding WFS1?
autosomal dominant ;
charged particles ;
diabetes mellitus ;
endoplasmic reticulum ;
optic atrophy ;
optic nerve ;
You may find definitions for these and many other terms in the Genetics Home Reference
- Aloi C, Salina A, Pasquali L, Lugani F, Perri K, Russo C, Tallone R, Ghiggeri GM, Lorini R, d'Annunzio G. Wolfram syndrome: new mutations, different phenotype. PLoS One. 2012;7(1):e29150. doi: 10.1371/journal.pone.0029150. Epub 2012 Jan 4. (http://www.ncbi.nlm.nih.gov/pubmed/22238590?dopt=Abstract)
- Bespalova IN, Van Camp G, Bom SJ, Brown DJ, Cryns K, DeWan AT, Erson AE, Flothmann K, Kunst HP, Kurnool P, Sivakumaran TA, Cremers CW, Leal SM, Burmeister M, Lesperance MM. Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss. Hum Mol Genet. 2001 Oct 15;10(22):2501-8. (http://www.ncbi.nlm.nih.gov/pubmed/11709537?dopt=Abstract)
- Cryns K, Pfister M, Pennings RJ, Bom SJ, Flothmann K, Caethoven G, Kremer H, Schatteman I, Köln KA, Tóth T, Kupka S, Blin N, Nürnberg P, Thiele H, van de Heyning PH, Reardon W, Stephens D, Cremers CW, Smith RJ, Van Camp G. Mutations in the WFS1 gene that cause low-frequency sensorineural hearing loss are small non-inactivating mutations. Hum Genet. 2002 May;110(5):389-94. Epub 2002 Apr 9. (http://www.ncbi.nlm.nih.gov/pubmed/12073007?dopt=Abstract)
- Cryns K, Sivakumaran TA, Van den Ouweland JM, Pennings RJ, Cremers CW, Flothmann K, Young TL, Smith RJ, Lesperance MM, Van Camp G. Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease. Hum Mutat. 2003 Oct;22(4):275-87. Review. (http://www.ncbi.nlm.nih.gov/pubmed/12955714?dopt=Abstract)
- Cryns K, Thys S, Van Laer L, Oka Y, Pfister M, Van Nassauw L, Smith RJ, Timmermans JP, Van Camp G. The WFS1 gene, responsible for low frequency sensorineural hearing loss and Wolfram syndrome, is expressed in a variety of inner ear cells. Histochem Cell Biol. 2003 Mar;119(3):247-56. Epub 2003 Feb 19. (http://www.ncbi.nlm.nih.gov/pubmed/12649740?dopt=Abstract)
- Eiberg H, Hansen L, Kjer B, Hansen T, Pedersen O, Bille M, Rosenberg T, Tranebjaerg L. Autosomal dominant optic atrophy associated with hearing impairment and impaired glucose regulation caused by a missense mutation in the WFS1 gene. J Med Genet. 2006 May;43(5):435-40. (http://www.ncbi.nlm.nih.gov/pubmed/16648378?dopt=Abstract)
- Finsterer J, Fellinger J. Nuclear and mitochondrial genes mutated in nonsyndromic impaired hearing. Int J Pediatr Otorhinolaryngol. 2005 May;69(5):621-47. Review. (http://www.ncbi.nlm.nih.gov/pubmed/15850684?dopt=Abstract)
- Gürtler N, Kim Y, Mhatre A, Schlegel C, Mathis A, Daniels R, Shelton C, Lalwani AK. Two families with nonsyndromic low-frequency hearing loss harbor novel mutations in Wolfram syndrome gene 1. J Mol Med (Berl). 2005 Jul;83(7):553-60. Epub 2005 May 24. (http://www.ncbi.nlm.nih.gov/pubmed/15912360?dopt=Abstract)
- Hofmann S, Bauer MF. Wolfram syndrome-associated mutations lead to instability and proteasomal degradation of wolframin. FEBS Lett. 2006 Jul 10;580(16):4000-4. Epub 2006 Jun 22. (http://www.ncbi.nlm.nih.gov/pubmed/16806192?dopt=Abstract)
- Hofmann S, Philbrook C, Gerbitz KD, Bauer MF. Wolfram syndrome: structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product. Hum Mol Genet. 2003 Aug 15;12(16):2003-12. (http://www.ncbi.nlm.nih.gov/pubmed/12913071?dopt=Abstract)
- Hogewind BF, Pennings RJ, Hol FA, Kunst HP, Hoefsloot EH, Cruysberg JR, Cremers CW. Autosomal dominant optic neuropathy and sensorineual hearing loss associated with a novel mutation of WFS1. Mol Vis. 2010 Jan 12;16:26-35. (http://www.ncbi.nlm.nih.gov/pubmed/20069065?dopt=Abstract)
- NCBI Gene (http://www.ncbi.nlm.nih.gov/gene/7466)
- Rendtorff ND, Lodahl M, Boulahbel H, Johansen IR, Pandya A, Welch KO, Norris VW, Arnos KS, Bitner-Glindzicz M, Emery SB, Mets MB, Fagerheim T, Eriksson K, Hansen L, Bruhn H, Möller C, Lindholm S, Ensgaard S, Lesperance MM, Tranebjaerg L. Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment. Am J Med Genet A. 2011 Jun;155A(6):1298-313. doi: 10.1002/ajmg.a.33970. Epub 2011 Apr 28. (http://www.ncbi.nlm.nih.gov/pubmed/21538838?dopt=Abstract)
- Rigoli L, Lombardo F, Di Bella C. Wolfram syndrome and WFS1 gene. Clin Genet. 2011 Feb;79(2):103-17. doi: 10.1111/j.1399-0004.2010.01522.x. Epub 2010 Aug 26. Review. (http://www.ncbi.nlm.nih.gov/pubmed/20738327?dopt=Abstract)
- Valéro R, Bannwarth S, Roman S, Paquis-Flucklinger V, Vialettes B. Autosomal dominant transmission of diabetes and congenital hearing impairment secondary to a missense mutation in the WFS1 gene. Diabet Med. 2008 Jun;25(6):657-61. doi: 10.1111/j.1464-5491.2008.02448.x. (http://www.ncbi.nlm.nih.gov/pubmed/18544103?dopt=Abstract)
The resources on this site should not be used as a substitute for
professional medical care or advice. Users seeking information about
a personal genetic disease, syndrome, or condition should consult with a qualified
See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.