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    WFS1 Gene

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    Submitted by: Hongliu Chen
    (This entry belongs to Entry Collection "MedlinePlus ")

    Definition

    Wolframin ER transmembrane glycoprotein.

    1. Normal Function

    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.

    2. Health Conditions Related to Genetic Changes

    2.1. Nonsyndromic Hearing Loss

    More than 30 WFS1 gene mutations have been identified in individuals with a form of nonsyndromic hearing loss 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.

    2.2. Wolfram Syndrome

    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 protein building blocks (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.

    2.3. Other Disorders

    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.

    3. Other Names for This Gene

    • DFNA14

    • DFNA38

    • DFNA6

    • DIDMOAD

    • WFRS

    • WFS

    • WFS1_HUMAN

    • Wolfram syndrome 1 (wolframin)

    The entry is from https://medlineplus.gov/genetics/gene/wfs1

    References

    1. 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.
    2. 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, BurmeisterM, Lesperance MM. Mutations in the Wolfram syndrome 1 gene (WFS1) are a commoncause of low frequency sensorineural hearing loss. Hum Mol Genet. 2001 Oct15;10(22):2501-8.
    3. 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 deHeyning PH, Reardon W, Stephens D, Cremers CW, Smith RJ, Van Camp G. Mutations inthe WFS1 gene that cause low-frequency sensorineural hearing loss are smallnon-inactivating mutations. Hum Genet. 2002 May;110(5):389-94.
    4. Cryns K, Sivakumaran TA, Van den Ouweland JM, Pennings RJ, Cremers CW,Flothmann K, Young TL, Smith RJ, Lesperance MM, Van Camp G. Mutational spectrumof the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetesmellitus, and psychiatric disease. Hum Mutat. 2003 Oct;22(4):275-87. Review.
    5. 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 frequencysensorineural hearing loss and Wolfram syndrome, is expressed in a variety ofinner ear cells. Histochem Cell Biol. 2003 Mar;119(3):247-56.
    6. Eiberg H, Hansen L, Kjer B, Hansen T, Pedersen O, Bille M, Rosenberg T,Tranebjaerg L. Autosomal dominant optic atrophy associated with hearingimpairment and impaired glucose regulation caused by a missense mutation in theWFS1 gene. J Med Genet. 2006 May;43(5):435-40.
    7. Finsterer J, Fellinger J. Nuclear and mitochondrial genes mutated innonsyndromic impaired hearing. Int J Pediatr Otorhinolaryngol. 2005May;69(5):621-47. Review.
    8. Gürtler N, Kim Y, Mhatre A, Schlegel C, Mathis A, Daniels R, Shelton C,Lalwani AK. Two families with nonsyndromic low-frequency hearing loss harbornovel mutations in Wolfram syndrome gene 1. J Mol Med (Berl). 2005Jul;83(7):553-60.
    9. Hofmann S, Bauer MF. Wolfram syndrome-associated mutations lead to instabilityand proteasomal degradation of wolframin. FEBS Lett. 2006 Jul 10;580(16):4000-4.
    10. Hofmann S, Philbrook C, Gerbitz KD, Bauer MF. Wolfram syndrome: structural andfunctional analyses of mutant and wild-type wolframin, the WFS1 gene product. HumMol Genet. 2003 Aug 15;12(16):2003-12.
    11. Hogewind BF, Pennings RJ, Hol FA, Kunst HP, Hoefsloot EH, Cruysberg JR,Cremers CW. Autosomal dominant optic neuropathy and sensorineual hearing lossassociated with a novel mutation of WFS1. Mol Vis. 2010 Jan 12;16:26-35.
    12. Rendtorff ND, Lodahl M, Boulahbel H, Johansen IR, Pandya A, Welch KO, NorrisVW, 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, TranebjaergL. Identification of p.A684V missense mutation in the WFS1 gene as a frequentcause 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.
    13. 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.Review.
    14. Valéro R, Bannwarth S, Roman S, Paquis-Flucklinger V, Vialettes B. Autosomaldominant 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.
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