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A 4bp-Insertion in the eya-Homologous Region (eyaHR) of EYA4 Causes Hearing Impairment in a Hungarian Family Linked to DFNA10

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Abstract

Background

Hereditary hearing impairment (HHI) is a heterogeneous class of disorders that shows various patterns of inheritance and involves a multitude of different genes. Mutations in the EYA4 gene are responsible for postlingual, progressive, autosomal dominant hearing loss at the DFNA10 locus. EYA4 is orthologous to the Drosophila gene eya (“eyes absent”), a key regulator of eye formation. EYA4 plays an important role in several developmental processes.

Material and Methods

Here we report a Hungarian family displaying sensorineural, progressive hearing impairment. The family comprising four generations with 11 affected and 8 unaffected members was subjected to genome-wide linkage analysis and candidate gene sequencing.

Results

By linkage analysis, the chromosomal region 6q22.3 was shown to segregate with the disease. Mutation analysis of the EYA4 gene, which maps to 6q22.3, revealed an insertion of 4 bp (1558insTTTG) in all affected family members. This insertion creates a frameshift and results in a stop codon at position 379. Hence, nearly the complete “eya homologous region” (eyaHR), which is essential for the protein function, would be deleted in the mutant EYA4 protein if the transcription were found to be stable.

Conclusions

This family is the third one linked to DFNA10 and revealing a mutation in the EYA4 gene. In all three families, the mutations are localized in different regions of the eyaHR, suggesting that this protein contains several functional subregions with different tissue-specific importance.

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References

  1. Fraser GR. (1971) The genetics of congenital deafness. Otolaryngol. Clin. North Am. 4: 227–247.

    CAS  PubMed  Google Scholar 

  2. Morton NE. (1991) Genetic epidemiology of hearing impairment. Ann N Y Acad Sci 630: 16–31.

    Article  CAS  Google Scholar 

  3. Van Camp G, Smith RJ. Hereditary hearing loss homepage. Available from: URL: https://doi.org/dnalab-www.uia.ac.be/dnalab/hhh/. Retrieved August, 2002.

  4. Wayne S, Robertson NG, De Clau F, et al. (2001) Mutations in the transcriptional activator EYA4 cause late-onset deafness at the DFNA10 locus. Hum. Mol. Genet. 10: 195–200.

    Article  CAS  Google Scholar 

  5. Hentze MW, Kulozik AE. (1999) A perfect message: RNA surveillance and nonsense-mediated decay. Cell. 96: 307–310.

    Article  CAS  Google Scholar 

  6. Borsani G, DeGrandi A, Ballabio A, et al. (1999) EYA4, a novel vertebrate gene related to Drosophila eyes absent. Hum. Mol. Genet. 8: 11–23.

    Article  CAS  Google Scholar 

  7. Lathrop G, Lalouel J. (1984) Easy calculations of lod scores and genetic risks on small computers. Am. J. Hum. Genet. 36: 460–465.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Sobel E, Lange K. (1996) Descent graphs in pedigree analysis: applications to haplotyping, locationscores, and marker-sharing statistics. Am. J. Hum. Genet. 58: 1323–1337.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Verstreken M, De Clau F, Schatteman I, et al. (2000) Audio-metric analysis of a Belgian family linked to the DFNA10 locus. Am. J. Otolaryngol. 21: 675–681.

    CAS  Google Scholar 

  10. Heanue TA, Reshef R, Davis RJ, et al. (1999) Synergistic regulation of vertebrate muscle development by Dach2, Eya2, and Six1, homologs of genes required for Drosophila eye formation. Genes Dev. 13: 3231–3243.

    Article  CAS  Google Scholar 

  11. Bonini NM, Leiserson WM, Benzer S. (1998) Multiple roles of the eyes absent gene in Drosophila. Dev. Biol. 196: 42–57.

    Article  CAS  Google Scholar 

  12. Bui QT, Zimmerman JE, Liu H, Bonini NM. (2000) Molecular analysis of Drosophila eyes absent mutants reveals features of the conserved Eya domain. Genetics 155: 709–720.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Heanue TA, Davis RJ, Rowitch, et al. (2002) Dach1, a vertebrate homologue of Drosophila dachshund, is expressed in the developing eye and ear of both chick and mouse and is regulated independently of Pax and Eya genes. Mech. Dev. 111: 75–87.

    Article  CAS  Google Scholar 

  14. Xu PX, Adams J, Peters H, Brown MC, Heaney S, Maas R. (1999) Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia. Nat. Genet. 23: 113–117.

    Article  CAS  Google Scholar 

  15. Clark SW, Fee BE, Cleveland JL. (2002) Misexpression of the eyes absent family triggers the apoptotic program. J. Biol. Chem. 277: 3560–3567.

    Article  CAS  Google Scholar 

  16. Morishita T, Makishima T, Kaneko C, et al. (2001) Deafness due to degeneration of cochlea neurons in caspase-3-deficient mice. Biochem. Biophys. Res. Commun. 284: 142–149.

    Article  CAS  Google Scholar 

  17. Takahashi K, Kamiya K, Urase K, et al. (2001) Caspase-3-deficiency induces hyperplasia of supporting cells and degeneration of sensory cells resulting in the hearing loss. Brain Res. 894: 359–367.

    Article  CAS  Google Scholar 

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Acknowledgments

This study was supported by grants of Else-Kröner-Fresenius-Stiftung, the Ministry of Education, Department for Research in Hungary (TeT 40/2000), and the Hungarian Basic Research Foundation (OTKA-T037255) and Dr. Karl Kuhn-Stiftung. We thank all patients for their cooperation in the study.

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Authors and Affiliations

  1. Department of Otolaryngology, Molecular Genetics, University of Tübingen, Elfriede-Aulhorn-Str. 5, 72076, Tübingen, Germany

    Markus Pfister, Birgit Haack, Hans-Peter Zenner & Susan Kupka

  2. Medical and Health Science Center, Department of Otolaryngology, University of Debrecen, Debrecen, Hungary

    Tímea Tóth

  3. Gene Mapping Center, Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany

    Holger Thiele, István Sziklai & Peter Nürnberg

  4. Department of Anthropology and Human Genetics, University of Tübingen, Tübingen, Germany

    Birgit Haack, Nikolaus Blin & Susan Kupka

  5. Institute for Medical Genetics, Charité, Humboldt University, Berlin, Germany

    Holger Thiele & Peter Nürnberg

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  1. Markus Pfister
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  2. Tímea Tóth
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  3. Holger Thiele
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  4. Birgit Haack
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  5. Nikolaus Blin
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  6. Hans-Peter Zenner
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  7. István Sziklai
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  8. Peter Nürnberg
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  9. Susan Kupka
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Correspondence to Susan Kupka.

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Pfister, M., Tóth, T., Thiele, H. et al. A 4bp-Insertion in the eya-Homologous Region (eyaHR) of EYA4 Causes Hearing Impairment in a Hungarian Family Linked to DFNA10. Mol Med 8, 607–611 (2002). https://doi.org/10.1007/BF03402171

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  • DOI: https://doi.org/10.1007/BF03402171

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