WFS1 explained

Wolframin is a protein that in humans is encoded by the WFS1 gene.^{[1] [2] [3]}

Function

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.^[3] Wolframin appears to function as a cation-selective ion channel.^[4]

Clinical significance

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 is characterized by non-immune insulin-dependent diabetes mellitus and bilateral progressive optic atrophy, usually presenting in childhood or early adult life. Diverse neurologic symptoms, including a predisposition to psychiatric illness, may also be associated with this disorder. A large number and variety of mutations in this gene, particularly in exon 8, can be associated with this syndrome. Mutations in this gene can also cause autosomal dominant deafness 6 (DFNA6), also known as DFNA14 or DFNA38.^[3]

Mutations in this gene have also been associated with congenital cataracts.^[5]

Further reading

• Khanim F, Kirk J, Latif F, Barrett TG . WFS1/wolframin mutations, Wolfram syndrome, and associated diseases. . Hum. Mutat. . 17 . 5 . 357–67 . 2001 . 11317350 . 10.1002/humu.1110 . 2944382 . free .
• Cryns K, Sivakumaran TA, Van den Ouweland JM, etal . Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease. . Hum. Mutat. . 22 . 4 . 275–87 . 2004 . 12955714 . 10.1002/humu.10258 . 39815754 . free .
• McHugh RK, Friedman RA . Genetics of hearing loss: Allelism and modifier genes produce a phenotypic continuum. . The Anatomical Record Part A: Discoveries in Molecular, Cellular, and Evolutionary Biology . 288 . 4 . 370–81 . 2006 . 16550584 . 10.1002/ar.a.20297 . free .
• Lesperance MM, Hall JW, Bess FH, etal . A gene for autosomal dominant nonsyndromic hereditary hearing impairment maps to 4p16.3. . Hum. Mol. Genet. . 4 . 10 . 1967–72 . 1996 . 8595423 . 10.1093/hmg/4.10.1967 .
• Strom TM, Hörtnagel K, Hofmann S, etal . Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein. . Hum. Mol. Genet. . 7 . 13 . 2021–8 . 1999 . 9817917 . 10.1093/hmg/7.13.2021 . free .
• Van Camp G, Kunst H, Flothmann K, etal . A gene for autosomal dominant hearing impairment (DFNA14) maps to a region on chromosome 4p16.3 that does not overlap the DFNA6 locus. . J. Med. Genet. . 36 . 7 . 532–6 . 1999 . 10424813 . 10.1136/jmg.36.7.532 . 1734405 .
• Hardy C, Khanim F, Torres R, etal . Clinical and molecular genetic analysis of 19 Wolfram syndrome kindreds demonstrating a wide spectrum of mutations in WFS1. . Am. J. Hum. Genet. . 65 . 5 . 1279–90 . 1999 . 10521293 . 10.1086/302609 . 1288280 .
• Furlong RA, Ho LW, Rubinsztein JS, etal . A rare coding variant within the wolframin gene in bipolar and unipolar affective disorder cases. . Neurosci. Lett. . 277 . 2 . 123–6 . 2000 . 10624825 . 10.1016/S0304-3940(99)00865-4 . 31662957 .
• Awata T, Inoue K, Kurihara S, etal . Missense variations of the gene responsible for Wolfram syndrome (WFS1/wolframin) in Japanese: possible contribution of the Arg456His mutation to type 1 diabetes as a nonautoimmune genetic basis. . Biochem. Biophys. Res. Commun. . 268 . 2 . 612–6 . 2000 . 10679252 . 10.1006/bbrc.2000.2169 .
• Ohtsuki T, Ishiguro H, Yoshikawa T, Arinami T . WFS1 gene mutation search in depressive patients: detection of five missense polymorphisms but no association with depression or bipolar affective disorder. . Journal of Affective Disorders . 58 . 1 . 11–7 . 2000 . 10760554 . 10.1016/S0165-0327(99)00099-3 .
• Gómez-Zaera M, Strom TM, Rodríguez B, etal . Presence of a major WFS1 mutation in Spanish Wolfram syndrome pedigrees. . Mol. Genet. Metab. . 72 . 1 . 72–81 . 2001 . 11161832 . 10.1006/mgme.2000.3107 .
• Kaytor EN, Zhu JL, Pao CI, Phillips LS . Physiological concentrations of insulin promote binding of nuclear proteins to the insulin-like growth factor I gene. . Endocrinology . 142 . 3 . 1041–9 . 2001 . 11181517 . 10.1210/endo.142.3.8046 . free .
• Takeda K, Inoue H, Tanizawa Y, etal . WFS1 (Wolfram syndrome 1) gene product: predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain. . Hum. Mol. Genet. . 10 . 5 . 477–84 . 2001 . 11181571 . 10.1093/hmg/10.5.477 . free .
• Tessa A, Carbone I, Matteoli MC, etal . Identification of novel WFS1 mutations in Italian children with Wolfram syndrome. . Hum. Mutat. . 17 . 4 . 348–9 . 2001 . 11295831 . 10.1002/humu.32 . 45109749 .
• Bespalova IN, Van Camp G, Bom SJ, etal . Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss. . Hum. Mol. Genet. . 10 . 22 . 2501–8 . 2002 . 11709537 . 6198816 . 10.1093/hmg/10.22.2501 .
• Young TL, Ives E, Lynch E, etal . Non-syndromic progressive hearing loss DFNA38 is caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1. . Hum. Mol. Genet. . 10 . 22 . 2509–14 . 2002 . 11709538 . 10.1093/hmg/10.22.2509 . free .
• Crawford J, Zielinski MA, Fisher LJ, etal . Is there a relationship between Wolfram syndrome carrier status and suicide? . Am. J. Med. Genet. . 114 . 3 . 343–6 . 2002 . 11920861 . 10.1002/ajmg.10256 .

External links

• GeneReviews/NCBI/NIH/UW entry on WFS1-Related Disorders

Notes and References

1. Polymeropoulos MH, Swift RG, Swift M . Linkage of the gene for Wolfram syndrome to markers on the short arm of chromosome 4 . Nat Genet . 8 . 1 . 95–7 . Jan 1995 . 7987399 . 10.1038/ng0994-95 . 13210147 .
2. Inoue H, Tanizawa Y, Wasson J, Behn P, Kalidas K, Bernal-Mizrachi E, Mueckler M, Marshall H, Donis-Keller H, Crock P, Rogers D, Mikuni M, Kumashiro H, Higashi K, Sobue G, Oka Y, Permutt MA . A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome) . Nat Genet . 20 . 2 . 143–8 . Oct 1998 . 9771706 . 10.1038/2441 . 11917210 .
3. Web site: WFS1 wolframin ER transmembrane glycoprotein [Homo sapiens (human) ]]. .
4. Osman AA, Saito M, Makepeace C, Permutt MA, Schlesinger P, Mueckler M . Wolframin expression induces novel ion channel activity in endoplasmic reticulum membranes and increases intracellular calcium . J. Biol. Chem. . 278 . 52 . 52755–62 . December 2003 . 14527944 . 10.1074/jbc.M310331200 . free .
5. Berry V, Gregory-Evans C, Emmett W, Waseem N, Raby J, Prescott D, Moore AT, Bhattacharya SS . Wolfram gene (WFS1) mutation causes autosomal dominant congenital nuclear cataract in humans . Eur. J. Hum. Genet. . 21. 12. 1356–60. March 2013 . 23531866 . 10.1038/ejhg.2013.52 . 3831071.