Abstract
Mutations in DFNA5 lead to autosomal dominant non-syndromic sensorineural hearing loss that starts at the high frequencies. To date, only three DFNA5 mutations have been described, and although different at the genomic DNA level, all lead to exon 8 skipping at the mRNA level. This remarkable fact has led towards the hypothesis that DFNA5-associated hearing loss is caused by a gain-of-function mutation and not by haplo-insufficiency as previously thought. Here, we describe a fourth DFNA5 mutation: the insertion of a cytosine at nucleotide position 640 (AF073308.1:_c.640insC, AAC69324.1:_p. Thr215HisfsX8). Unlike the previously described mutations, this frameshift mutation truncates the protein in exon 5 of the gene. Although the mutation was found in an extended Iranian family with hereditary hearing loss, it does not segregate with the hearing loss phenotype and is even present in persons with normal hearing. This fact provides further support for the hypothesis that DFNA5-associated hearing loss is caused by a gain-of-function mutation.
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Bischoff AMLC, Luijendijk MWJ, Huygen PLM, van Duijnhoven G, De Leenheer EMR, Oudesluijs G, Van Laer L, Cremers FPM, Cremers CWRJ, Kremer H (2004) A second mutation identified in the DFNA5 gene in a Dutch family. A clinical and genetic evaluation. Audiol Neurootol 9:34–36
Duno M, Hove H, Kirchhoff M, Devriendt K, Schwartz M (2004) Mapping genomic deletions down to the base: a quantitative copy number scanning approach used to characterise and clone the breakpoints of a recurrent 7p14.2p15.3 deletion. Hum Genet 115:459–467
Gregan J, Van Laer L, Lieto LD, Van Camp G, Kearsey SE (2003) A yeast model for the study of human DFNA5, a gene mutated in nonsyndromic hearing impairment. Biochim Biophys Acta 1638:179–186
Van Laer L, Huizing EH, Verstreken M, van Zuijlen D, Wauters JG, Bossuyt PJ, Van de Heyning P, McGuirt WT, Smith RJH, Willems PJ, Legan PK, Richardson GP, Van Camp G (1998) Nonsyndromic hearing impairment is associated with a mutation in DFNA5. Nat Genet 20:194–197
Van Laer L, DeStefano AL, Myers RH, Flothmann K, Thys S, Fransen E, Gates GA, Van Camp G, Baldwin CT (2002) Is DFNA5 a susceptibility gene for age-related hearing impairment? Eur J Hum Genet 10:883–886
Van Laer L, Vrijens K, Thys S, Van Tendeloo VFI, Smith RJH, Van Bockstaele DR, Timmermans J-P, Van Camp G (2004) DFNA5: hearing impairment exon instead of hearing impairment gene? J Med Genet 41:401–406
Van Laer L, Pfister M, Thys S, Vrijens K, Mueller M, Umans L, Serneels L, Van Nassauw L, Kooy F, Smith RJH, Timmermans JP, Van Leuven F, Van Camp G (2005) Mice lacking Dfna5 show a diverging number of cochlear fourth row outer hair cells. Neurobiol Dis 19:386–399
Yu C, Meng X, Zhang S, Zhao G, Hu L, Kong X (2003) A 3-nucleotide deletion in the polypyrimidine tract of intron 7 of the DFNA5 gene causes nonsyndromic hearing impairment in a Chinese family. Genomics 82:575–579
Acknowledgments
This work is supported in part by FWO grant 1.5.048.05N and by the European Commission FP6 Integrated Project: EUROHEAR (LSHG-CT-20054–512063). R.J.H.S. was supported in part by National Institutes of Health grant RO1 DC03544 and H.N. by grant P6193 of the Iran Deputy of Research and Technology of the Ministry of Health and Medical Education.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Van Laer, L., Meyer, N.C., Malekpour, M. et al. A novel DFNA5 mutation does not cause hearing loss in an Iranian family. J Hum Genet 52, 549–552 (2007). https://doi.org/10.1007/s10038-007-0137-2
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1007/s10038-007-0137-2
Keywords
This article is cited by
-
Further evidence for “gain-of-function” mechanism of DFNA5 related hearing loss
Scientific Reports (2018)
-
Diverse spectrum of rare deafness genes underlies early-childhood hearing loss in Japanese patients: a cross-sectional, multi-center next-generation sequencing study
Orphanet Journal of Rare Diseases (2013)
-
The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein
European Journal of Human Genetics (2011)
-
Evidence for a founder mutation causing DFNA5 hearing loss in East Asians
Journal of Human Genetics (2010)
-
The genetic bases for non-syndromic hearing loss among Chinese
Journal of Human Genetics (2009)
