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Vol. 18, No. 6, 2013
Issue release date: November 2013

A Novel Otoferlin Splice-Site Mutation in Siblings with Auditory Neuropathy Spectrum Disorder

Runge C.L. · Erbe C.B. · McNally M.T. · Van Dusen C. · Friedland D.R. · Kwitek A.E. · Kerschner J.E.
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Abstract

We characterize a novel otoferlin mutation discovered in a sibling pair diagnosed with auditory neuropathy spectrum disorder and investigate auditory nerve function through their cochlear implants. Genetic sequencing revealed a homozygous mutation at the otoferlin splice donor site of exon 28 (IVS28 + 1G>T) in both siblings. Functional investigation showed that the intronic sequence between exons 28 and 29 was retained in the mutated minigenes that were expressed in 293T cells. Auditory nerve compound action potential recovery functions in the siblings demonstrated different rates of neural recovery, with sibling AN1 showing rapid recovery (1.14 ms) and AN2 showing average recovery (0.78 ms) compared to subjects with sensorineural hearing loss (average: adults 0.71 ms, children 0.85 ms). Differences in neural recovery were consistent with speech perception differences between the siblings. Genotype information may indicate site of lesion in hearing loss; however, additional, as yet, unknown factors may impact clinical outcomes and must be considered. © 2013 S. Karger AG, Basel



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References

  1. Abbas PJ, Brown CJ: Electrically evoked auditory brainstem response: refractory properties and strength-duration functions. Hear Res 1991;51:139-147.
  2. Adato A, Raskin L, Petit C, Bonne-Tamir B: Deafness heterogeneity in a Druze isolate from the Middle East: novel OTOF and PDS mutations, low prevalence of GJB2 35delG mutation and indication for a new DFNB locus. Eur J Hum Genet 2000;8:437-442.
  3. Berget SM: Exon recognition in vertebrate splicing. J Biol Chem 1995;270:2411-2414.
  4. Botros A, Psarros C: Neural response telemetry reconsidered. I. The relevance of ECAP threshold profiles and scaled profiles to cochlear implant fitting. Ear Hear 2010a;31:367-379.
  5. Botros A, Psarros C: Neural response telemetry reconsidered. II. The influence of neural population on the ECAP recovery function and refractoriness. Ear Hear 2010b;31:380-391.
  6. Brown CJ, Abbas PJ, Borland J, Bertschy MR: Electrically evoked whole nerve action potentials in Ineraid cochlear implant users: responses to different stimulating electrode configurations and comparison to psychophysical responses. J Speech Hear Res 1996;39:453-467.

    External Resources

  7. Brown CJ, Abbas PJ, Gantz B: Electrically evoked whole-nerve action potentials: data from human cochlear implant users. J Acoust Soc Am 1990;88:1385-1391.
  8. Buss E, Labadie RF, Brown CJ, Gross AJ, Grose JH, Pillsbury HC: Outcome of cochlear implantation in pediatric auditory neuropathy. Otol Neurotol 2002;23:328-332.
  9. Chiu YH, Wu CC, Lu YC, Chen PJ, Lee WY, Liu AY, Hsu CJ: Mutations in the OTOF gene in Taiwanese patients with auditory neuropathy. Audiol Neurootol 2010;15:364-374.
  10. Choi BY, Ahmed ZM, Riazuddin S, Bhinder MA, Shahzad M, Husnain T, Griffith AJ, Friedman TB: Identities and frequencies of mutations of the otoferlin gene (OTOF) causing DFNB9 deafness in Pakistan. Clin Genet 2009;75:237-243.
  11. Cooper TA, Wan L, Dreyfuss G: RNA and disease. Cell 2009;136:777-793.
  12. Fulmer SL, Runge CL, Jensen JW, Friedland DR: Rate of neural recovery in implanted children with auditory neuropathy spectrum disorder. Otolaryngol Head Neck Surg 2011;144:274-279.
  13. Garadat SN, Litovsky RY: Speech intelligibility in free field: spatial unmasking in preschool children. J Acoust Soc Am 2007;121:1047-1055.
  14. Hertel KJ: Combinatorial control of exon recognition. J Biol Chem 2008;283:1211-1215.
  15. Houseman MJ, Jackson AP, Al-Gazali LI, Badin RA, Roberts E, Mueller RF: A novel mutation in a family with non-syndromic sensorineural hearing loss that disrupts the newly characterised OTOF long isoforms. J Med Genet 2001;38:E25.
  16. Kiefer J, Hohl S, Sturzebecher E, Pfennigdorff T, Gstoettner W: Comparison of speech recognition with different speech coding strategies (SPEAK, CIS, and ACE) and their relationship to telemetric measures of compound action potentials in the nucleus CI 24M cochlear implant system. Audiology 2001;40:32-42.
  17. Kim JR, Kim LS, Jeong SW, Kim JS, Chung SH: Recovery function of electrically evoked compound action potential in implanted children with auditory neuropathy: preliminary results. Acta Otolaryngol 2011;131:796-801.
  18. Kirk KI, Pisoni DB, Osberger MJ: Lexical effects on spoken word recognition by pediatric cochlear implant users. Ear Hear 1995;16:470-481.

    External Resources

  19. Lee ER, Friedland DR, Runge CL: Recovery from forward masking in elderly cochlear implant users. Otol Neurotol 2012;33:355-363.
  20. Levitt H: Transformed up-down methods in psychoacoustics. J Acoust Soc Am 1971;49(suppl 2):467.

    External Resources

  21. Loundon N, Marcolla A, Roux I, Rouillon I, Denoyelle F, Feldmann D, Marlin S, Garabedian EN: Auditory neuropathy or endocochlear hearing loss? Otol Neurotol 2005;26:748-754.
  22. Marlin S, Feldmann D, Nguyen Y, Rouillon I, Loundon N, Jonard L, Bonnet C, Couderc R, Garabedian EN, Petit C, Denoyelle F: Temperature-sensitive auditory neuropathy associated with an otoferlin mutation. Deafening fever! Biochem Biophys Res Commun 2010;394:737-742.
  23. Mason JC, De Michele A, Stevens C, Ruth RA, Hashisaki GT: Cochlear implantation in patients with auditory neuropathy of varied etiologies. Laryngoscope 2003;113:45-49.
  24. Migliosi V, Modamio-Hoybjor S, Moreno-Pelayo MA, Rodriguez-Ballesteros M, Villamar M, Telleria D, Menendez I, Moreno F, Del Castillo I: Q829X, a novel mutation in the gene encoding otoferlin (OTOF), is frequently found in Spanish patients with prelingual non-syndromic hearing loss. J Med Genet 2002;39:502-506.
  25. Mirghomizadeh F, Pfister M, Apaydin F, Petit C, Kupka S, Pusch CM, Zenner HP, Blin N: Substitutions in the conserved C2C domain of otoferlin cause DFNB9, a form of nonsyndromic autosomal recessive deafness. Neurobiol Dis 2002;10:157-164.
  26. Nakai K, Sakamoto H: Construction of a novel database containing aberrant splicing mutations of mammalian genes. Gene 1994;141:171-177.
  27. Pelosi S, Rivas A, Haynes DS, Bennett ML, Labadie RF, Hedley-Williams A, Wanna GB: Stimulation rate reduction and auditory development in poorly performing cochlear implant users with auditory neuropathy. Otol Neurotol 2012;33:1502-1506.
  28. Peterson A, Shallop J, Driscoll C, Breneman A, Babb J, Stoeckel R, Fabry L: Outcomes of cochlear implantation in children with auditory neuropathy. J Am Acad Audiol 2003;14:188-201.

    External Resources

  29. Rance G, McKay C, Grayden D: Perceptual characterization of children with auditory neuropathy. Ear Hear 2004;25:34-46.
  30. Rodriguez-Ballesteros M, del Castillo FJ, Martin Y, Moreno-Pelayo MA, Morera C, Prieto F, Marco J, Morant A, Gallo-Teran J, Morales-Angulo C, Navas C, Trinidad G, Tapia MC, Moreno F, del Castillo I: Auditory neuropathy in patients carrying mutations in the otoferlin gene (OTOF). Hum Mutat 2003;22:451-456.
  31. Rodriguez-Ballesteros M, Reynoso R, Olarte M, Villamar M, Morera C, Santarelli R, Arslan E, Meda C, Curet C, Volter C, Sainz-Quevedo M, Castorina P, Ambrosetti U, Berrettini S, Frei K, Tedin S, Smith J, Cruz Tapia M, Cavalle L, Gelvez N, Primignani P, Gomez-Rosas E, Martin M, Moreno-Pelayo MA, Tamayo M, Moreno-Barral J, Moreno F, del Castillo I: A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy. Hum Mutat 2008;29:823-831.
  32. Romanos J, Kimura L, Favero ML, Izarra FA, de Mello Auricchio MT, Batissoco AC, Lezirovitz K, Abreu-Silva RS, Mingroni-Netto RC: Novel OTOF mutations in Brazilian patients with auditory neuropathy. J Hum Genet 2009;54:382-385.
  33. Rouillon I, Marcolla A, Roux I, Marlin S, Feldmann D, Couderc R, Jonard L, Petit C, Denoyelle F, Garabedian EN, Loundon N: Results of cochlear implantation in two children with mutations in the OTOF gene. Int J Pediatr Otorhinolaryngol 2006;70:689-696.
  34. Roux I, Safieddine S, Nouvian R, Grati M, Simmler MC, Bahloul A, Perfettini I, Le Gall M, Rostaing P, Hamard G, Triller A, Avan P, Moser T, Petit C: Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse. Cell 2006;127:277-289.
  35. Runge-Samuelson CL, Drake S, Wackym PA: Quantitative analysis of electrically evoked auditory brainstem responses in implanted children with auditory neuropathy/dyssynchrony. Otol Neurotol 2008;29:174-178.
  36. Sakharkar MK, Chow VT, Kangueane P: Distributions of exons and introns in the human genome. In Silico Biol 2004;4:387-393.

    External Resources

  37. Santarelli R, Del Castillo I, Rodriguez-Ballesteros M, Scimemi P, Cama E, Arslan E, Starr A: Abnormal cochlear potentials from deaf patients with mutations in the otoferlin gene. J Assoc Res Otolaryngol 2009;10:545-556.
  38. Shallop JK, Jin SH, Driscoll CL, Tibesar RJ: Characteristics of electrically evoked potentials in patients with auditory neuropathy/auditory dys-synchrony. Int J Audiol 2004;43(suppl 1):S22-S27.

    External Resources

  39. Shallop JK, Peterson A, Facer GW, Fabry LB, Driscoll CL: Cochlear implants in five cases of auditory neuropathy: postoperative findings and progress. Laryngoscope 2001;111:555-562.
  40. Starr A, Picton TW, Sininger Y, Hood LJ, Berlin CI: Auditory neuropathy. Brain 1996;119:741-753.
  41. Starr A, Sininger Y, Winter M, Derebery MJ, Oba S, Michalewski HJ: Transient deafness due to temperature-sensitive auditory neuropathy. Ear Hear 1998;19:169-179.
  42. Sterner DA, Carlo T, Berget SM: Architectural limits on split genes. Proc Natl Acad Sci USA 1996;93:15081-15085.
  43. Tekin M, Akcayoz D, Incesulu A: A novel missense mutation in a C2 domain of OTOF results in autosomal recessive auditory neuropathy. Am J Med Genet A 2005;138:6-10.
  44. Varga R, Avenarius MR, Kelley PM, Keats BJ, Berlin CI, Hood LJ, Morlet TG, Brashears SM, Starr A, Cohn ES, Smith RJ, Kimberling WJ: OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele. J Med Genet 2006;43:576-581.
  45. Varga R, Kelley PM, Keats BJ, Starr A, Leal SM, Cohn E, Kimberling WJ: Non-syndromic recessive auditory neuropathy is the result of mutations in the otoferlin (OTOF) gene. J Med Genet 2003;40:45-50.
  46. Yasunaga S, Grati M, Chardenoux S, Smith TN, Friedman TB, Lalwani AK, Wilcox ER, Petit C: OTOF encodes multiple long and short isoforms: genetic evidence that the long ones underlie recessive deafness DFNB9. Am J Hum Genet 2000;67:591-600.
  47. Yasunaga S, Grati M, Cohen-Salmon M, El-Amraoui A, Mustapha M, Salem N, El-Zir E, Loiselet J, Petit C: A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness. Nat Genet 1999;21:363-369.
  48. Zeng FG, Kong YY, Michalewski HJ, Starr A: Perceptual consequences of disrupted auditory nerve activity. J Neurophysiol 2005;93:3050-3063.
  49. Zeng FG, Oba S, Garde S, Sininger Y, Starr A: Temporal and speech processing deficits in auditory neuropathy. Neuroreport 1999;10:3429-3435.

    External Resources



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