Mutation Update

Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease†

  1. Kim Cryns1,‡,
  2. Theru A. Sivakumaran2,‡,
  3. Jody M.W. Van den Ouweland3,
  4. Ronald J.E. Pennings4,
  5. Cor W.R.J. Cremers4,
  6. Kris Flothmann1,
  7. Terry-Lynn Young5,
  8. Richard J.H. Smith6,
  9. Marci M. Lesperance2,
  10. Guy Van Camp1,*

Article first published online: 26 AUG 2003

DOI: 10.1002/humu.10258

Issue

Human Mutation

Human Mutation

Volume 22, Issue 4, pages 275–287, October 2003

Additional Information

How to Cite

Cryns, K., Sivakumaran, T. A., Van den Ouweland, J. M.W., Pennings, R. J.E., Cremers, C. W.R.J., Flothmann, K., Young, T.-L., Smith, R. J.H., Lesperance, M. M. and Camp, G. V. (2003), Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease. Hum. Mutat., 22: 275–287. doi: 10.1002/humu.10258

Author Information

  1. 1

    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium

  2. 2

    Department of Otolaryngology-Head and Neck Surgery, University of Michigan Health System, Ann Arbor, Michigan

  3. 3

    Department of Pathology and Laboratory Medicine, University Hospital Groningen, Groningen, The Netherlands

  4. 4

    Department of Otorhinolaryngology, UMC St. Radboud, Nijmegen, The Netherlands

  5. 5

    Department of Genomic Sciences and Medicine, University of Washington, Seattle, Washington

  6. 6

    Molecular Otolaryngology Research Laboratories, Department of Otolaryngology, University of Iowa, Iowa City, Iowa

  1. ‡

    Kim Cryns and Theru A. Sivakumaran contributed equally to this work.

*Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium

  1. †

    Communicated by Richard G.H. Cotton

Publication History

  1. Issue published online: 26 AUG 2003
  2. Article first published online: 26 AUG 2003
  3. Manuscript Accepted: 30 APR 2003
  4. Manuscript Received: 27 JAN 2003

Funded by

  • the Heinsius Houbolt Foundation
  • NIH. Grant Number: R01 DC01076
  • the FWO. Grant Number: G.0277.01

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Keywords:

  • WFS1;
  • WFS2;
  • Wolfram syndrome;
  • DFNA6;
  • DFNA14;
  • diabetes mellitus;
  • psychiatric diseases;
  • genotype–phenotype correlation

Abstract

WFS1 is a novel gene and encodes an 890 amino-acid glycoprotein (wolframin), predominantly localized in the endoplasmic reticulum. Mutations in WFS1 underlie autosomal recessive Wolfram syndrome and autosomal dominant low frequency sensorineural hearing impairment (LFSNHI) DFNA6/14. In addition, several WFS1 sequence variants have been shown to be significantly associated with diabetes mellitus and this gene has also been implicated in psychiatric diseases. Wolfram syndrome is highly variable in its clinical manifestations, which include diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Wolfram syndrome mutations are spread over the entire coding region, and are typically inactivating, suggesting that a loss of function causes the disease phenotype. In contrast, only non-inactivating mutations have been found in DFNA6/14 families, and these mutations are mainly located in the C-terminal protein domain. In this paper, we provide an overview of the currently known disease-causing and benign allele variants of WFS1 and propose a potential genotype–phenotype correlation for Wolfram syndrome and LFSNHI. Hum Mutat 22:275–287, 2003. © 2003 Wiley-Liss, Inc.

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