Journal of Molecular Medicine

, Volume 83, Issue 7, pp 553–560 | Cite as

Two families with nonsyndromic low-frequency hearing loss harbor novel mutations in Wolfram syndrome gene 1

  • Nicolas Gürtler
  • Yuil Kim
  • Anand Mhatre
  • Christoph Schlegel
  • Adolf Mathis
  • Robert Daniels
  • Clough Shelton
  • Anil K. Lalwani
Original Article


Although hereditary hearing loss is highly heterogeneous, only a few loci have been implicated with low-frequency hearing loss. Mutations in one single gene, Wolfram syndrome 1 (WFS1), have been reported to account for most familial cases with this type of hearing impairment. This study was conducted to determine the cause of nonsyndromic low-frequency hereditary hearing impairment in two large families. Two large families from Switzerland and United States with low-frequency hearing loss were identified. Genomewide linkage analysis was performed followed by mutation screening in the candidate gene WFS1 with direct DNA sequencing and restriction fragment analysis. Both families were linked to DFNA6/14/38 with lod scores>3. Two novel heterozygous missense mutations in WFS1 were identified: c.2311G>C leading to p.D771H in the Swiss family and c.2576G>C leading to p.R859P in the US family. The sequence alteration was absent in 100 control chromosomes. Nonsyndromic low-frequency hereditary hearing impairment seems to be predominantly a monogenic disorder due to WFS1. We confirm that most mutations in WFS1 associated with isolated low-frequency hearing loss are clustered in the C-terminal protein domain coded by exon 8.


Wolfram syndrome gene 1 Nonsyndromic hereditary hearing impairment Low-frequency hearing loss 


  1. 1.
    Van Camp G, Smith R Hereditary hearing loss homepage.
  2. 2.
    Lesperance MM, Hall JW III, Bess FH et al (1995) A gene for autosomal dominant nonsyndromic hereditary hearing impairment maps to 4p16.3. Hum Mol Genet 4:1967–1972PubMedGoogle Scholar
  3. 3.
    Van Camp G, Kunst H, Flothmann K et al (1999) 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 36:532–536PubMedGoogle Scholar
  4. 4.
    Lynch ED, Lee MK, Morrow JE, Welcsh PL, Leon PE, King MC (1997) Nonsyndromic deafness DFNA1 associated with mutation of a human homolog of the Drosophila gene diaphanous. Science 278:1315–1318CrossRefPubMedGoogle Scholar
  5. 5.
    Young TL, Ives E, Lynch E et al (2001) Non-syndromic progressive hearing loss DFNA38 is caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1. Hum Mol Genet 10:2509–2514CrossRefPubMedGoogle Scholar
  6. 6.
    Gürtler Nea, Kim Y, Mhatre A, Schlegel C, Mathis A, Lalwani AK (2004) DFNA54, a third locus for low-frequency hearing loss. J Mol Med 82:775–780CrossRefPubMedGoogle Scholar
  7. 7.
    Bespalova IN, Van Camp G, Bom SJH et al (2001) Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss. Hum Mol Genet 10:2501–2508CrossRefPubMedGoogle Scholar
  8. 8.
    Inoue H, Tanizawa Y, Wasson J et al (1998) A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet 20:143–148CrossRefPubMedGoogle Scholar
  9. 9.
    Osman AA, Saito M, Makepeace C, Permutt MA, Schlesinger P, Mueckler M (2003) Wolframin expression induces novel ion channel activity in endoplasmic reticulum membranes and increases intracellular calcium. J Biol Chem 278:52755–52762CrossRefPubMedGoogle Scholar
  10. 10.
    Takeda K, Inoue H, Tanizawa Y et al (2001) WFS1 (Wolfram syndrome 1) gene product: predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain. Hum Mol Genet 10:477–484CrossRefPubMedGoogle Scholar
  11. 11.
    Hofmann S, Philbrook C, Gerbitz KD, Bauer MF (2003) Wolfram syndrome: structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product. Hum Mol Genet 12:2003–2012CrossRefPubMedGoogle Scholar
  12. 12.
    Ott J. Genetic linkage programs.
  13. 13.
    Strom TM, Hortnagel K, Hofmann S et al (1998) 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 7:2021–2028CrossRefPubMedGoogle Scholar
  14. 14.
    Heffner RS, Koay G, Heffner HE (2001) Audiograms of five species of rodents: implications for the evolution of hearing and the perception of pitch. Hear Res 157:138–152CrossRefPubMedGoogle Scholar
  15. 15.
    Raphael Y, Altschuler RA (2003) Structure and innervation of the cochlea. Brain Res Bull 60:397–422CrossRefPubMedGoogle Scholar
  16. 16.
    Cryns K, Pfister M, Pennings RJ et al (2002) Mutations in the WFS1 gene that cause low-frequency sensorineural hearing loss are small non-inactivating mutations. Hum Genet 110:389–394CrossRefPubMedGoogle Scholar
  17. 17.
    Torres R, Leroy E, Hu X et al (2001) Mutation screening of the Wolfram syndrome gene in psychiatric patients. Mol Psychiatry 6:39–43CrossRefPubMedGoogle Scholar
  18. 18.
    Kunz J, Marquez-Klaka B, Uebe S, Volz-Peters A, Berger R, Rausch P (2003) Identification of a novel mutation in WFS1 in a family affected by low-frequency hearing impairment. Mutat Res 525:121–124PubMedGoogle Scholar
  19. 19.
    Komatsu K, Nakamura N, Ghadami M et al (2002) Confirmation of genetic homogeneity of nonsyndromic low-frequency sensorineural hearing loss by linkage analysis and a DFNA6/14 mutation in a Japanese family. J Hum Genet 47:395–399CrossRefPubMedGoogle Scholar
  20. 20.
    Hardy C, Khanim F, Torres R et al (1999) Clinical and molecular genetic analysis of 19 Wolfram syndrome kindreds demonstrating a wide spectrum of mutations in WFS1. Am J Hum Genet 65:1279–1290CrossRefPubMedGoogle Scholar
  21. 21.
    van den Ouweland JM, Cryns K, Pennings RJ et al (2003) Molecular characterization of WFS1 in patients with Wolfram syndrome. J Mol Diagn 5:88–95PubMedGoogle Scholar
  22. 22.
    Bykhovskaya Y, Estivill X, Taylor K et al (2000) Candidate locus for a nuclear modifier gene for maternally inherited deafness. Am J Hum Genet 66:1905–1910CrossRefPubMedGoogle Scholar
  23. 23.
    Ikeda A, Zheng QY, Rosenstiel P et al (1999) Genetic modification of hearing in tubby mice: evidence for the existence of a major gene (moth1) which protects tubby mice from hearing loss. Hum Mol Genet 8:1761–1767CrossRefPubMedGoogle Scholar
  24. 24.
    Riazuddin S, Castelein CM, Ahmed ZM et al (2000) Dominant modifier DFNM1 suppresses recessive deafness DFNB26. Nat Genet 26:431–434CrossRefPubMedGoogle Scholar
  25. 25.
    Lesperance MM, Hall JW III, San Agustin TB, Leal SM (2003) Mutations in the Wolfram syndrome type 1 gene (WFS1) define a clinical entity of dominant low-frequency sensorineural hearing loss. Arch Otolaryngol Head Neck Surg 129:411–420CrossRefPubMedGoogle Scholar
  26. 26.
    Pennings RJ, Bom SJ, Cryns K et al (2003) Progression of low-frequency sensorineural hearing loss (DFNA6/14-WFS1). Arch Otolaryngol Head Neck Surg 129:421–426CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Nicolas Gürtler
    • 1
    • 2
  • Yuil Kim
    • 2
  • Anand Mhatre
    • 2
    • 3
  • Christoph Schlegel
    • 4
  • Adolf Mathis
    • 4
  • Robert Daniels
    • 5
    • 6
  • Clough Shelton
    • 5
    • 6
  • Anil K. Lalwani
    • 2
    • 3
    • 7
  1. 1.Hals-Nasen-Ohren-KlinikKantonsspital AarauAarauSwitzerland
  2. 2.Laboratory of Molecular Otology, Epstein Laboratories, Department of Otolaryngology–Head and Neck SurgeryUniversity of California–San FranciscoSan FranciscoUSA
  3. 3.Laboratory of Molecular Otology, Department of OtolaryngologyNew York UniversityNew YorkUSA
  4. 4.Hals-Nasen-Ohren-KlinikKantonsspital LuzernLucerneSwitzerland
  5. 5.Department of OtolaryngologyUniversity of UtahSalt Lake CityUSA
  6. 6.Michigan Ear Center Department of SurgeryMichigan State UniversityEast LansingUSA
  7. 7.Department of OtolaryngologyNYU School of MedicineNew YorkUSA

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