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Research progress in pathogenic genes of hereditary non-syndromic mid-frequency deafness

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Abstract

Hearing impairment is considered as the most prevalent impairment worldwide. Almost 600 million people in the world suffer from mild or moderate hearing impairment, an estimated 10% of the human population. Genetic factors play an important role in the pathogenesis of this disorder. Hereditary hearing loss is divided into syndromic hearing loss (associated with other anomalies) and non-syndromic hearing loss (not associated with other anomalies). Approximately 80% of genetic deafness is non-syndromic. On the basis of the frequency of hearing loss, hereditary non-syndromic hearing loss can be divided into high-, mid-, low-, and total-frequency hearing loss. An audiometric finding of mid-frequency sensorineural hearing loss, or a “bowl-shaped” audiogram, is uncommon. Up to now, merely 7 loci have been linked to mid-frequency hearing loss. Only four genetic midfrequency deafness genes, namely, DFNA10 (EYA4), DFNA8/12 (TECTA), DFNA13 (COL11A2), DFNA44 (CCDC50), have been reported to date. This review summarizes the research progress of the four genes to draw attention to mid-frequency deafness genes.

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References

  1. Sang Q, Mei H, Kuermanhan A, Feng R, Guo L, Qu R, Xu Y, Li H, Jin L, He L, Wang L. Identification of a novel compound heterozygous mutation in PTPRQ in a DFNB84 family with prelingual sensorineural hearing impairment. Mol Genet Genomics 2015; 290(3): 1135–1139

    Article  CAS  PubMed  Google Scholar 

  2. Wu W, Lü J, Li Y, Kam AC, Fai Tong MC, Huang Z, Wu H. A new hearing screening system for preschool children. Int J Pediatr Otorhinolaryngol 2014; 78(2): 290–295

    Article  PubMed  Google Scholar 

  3. Sun XB, Wei ZY, Yu LM, Wang Q, Liang W. Prevalence and etiology of people with hearing impairment in China. Chin J Epidemiol (Zhonghua Liu Xing Bing Xue Za Zhi) 2008; 29: 643–646 (in Chinese)

    Google Scholar 

  4. Rosenberg C, Freitas EL, Uehara DT, Auricchio MT, Costa SS, Oiticica J, Silva AG, Krepischi AC, Mingroni-Netto RC. Clinical genetics genomic copy number alterations in non-syndromic hearing loss. Clin Genet 2015 Oct 12. [Epub ahead of print] doi: 10.1111/cge.12683

    Google Scholar 

  5. Atik T, Onay H, Aykut A, Bademci G, Kirazli T, Tekin M, Ozkinay F. Comprehensive analysis of deafness genes in families with autosomal recessive nonsyndromic hearing loss. PLoS ONE 2015; 10(11): e0142154

    Article  PubMed  PubMed Central  Google Scholar 

  6. Catelani AL, Krepischi AC, Kim CA, Kok F, Otto PA, Auricchio MT, Mazzeu JF, Uehara DT, Costa SS, Knijnenburg J, Tabith A Jr, Vianna-Morgante AM, Mingroni-Netto RC, Rosenberg C. Chromosome imbalances in syndromic hearing loss. Clin Genet 2009; 76(5): 458–464

    Article  CAS  PubMed  Google Scholar 

  7. Shearer AE, Kolbe DL, Azaiez H, Sloan CM, Frees KL, Weaver AE, Clark ET, Nishimura CJ, Black-Ziegelbein EA, Smith RJ. Copy number variants are a common cause of non-syndromic hearing loss. Genome Med 2014; 6(5): 37

    Article  PubMed  PubMed Central  Google Scholar 

  8. Bahmad F, O'Malley J, Tranebjaerg L, Merchant SN. Histopathology of nonsyndromic autosomal dominant midfrequency sensorineural hearing loss. Otol Neurotol 2008; 29(5): 601–606

    Article  PubMed  PubMed Central  Google Scholar 

  9. Mustapha M, Weil D, Chardenoux S, Elias S, El-Zir E, Beckmann JS, Loiselet J, Petit C. An a-tectorin gene defect causes a newly identified autosomal recessive form of sensorineural pre-lingual non-syndromic deafness, DFNB21. Hum Mol Genet 1999; 8(3): 409–412

    Article  CAS  PubMed  Google Scholar 

  10. Verhoeven K, Van Laer L, Kirschhofer K, Legan PK, Hughes DC, Schatteman I, Verstreken M, Van Hauwe P, Coucke P, Chen A, Smith RJ, Somers T, Offeciers FE, Van de Heyning P, Richardson GP, Wachtler F, Kimberling WJ, Willems PJ, Govaerts PJ, Van Camp G. Mutations in the human a-tectorin gene cause autosomal dominant non-syndromic hearing impairment. Nat Genet 1998; 19(1): 60–62

    Article  CAS  PubMed  Google Scholar 

  11. Legan PK, Goodyear RJ, Morín M, Mencia A, Pollard H, Olavarrieta L, Korchagina J, Modamio-Hoybjor S, Mayo F, Moreno F, Moreno-Pelayo MA, Richardson GP. Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane. Hum Mol Genet 2014; 23(10): 2551–2568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hughes DC, Legan PK, Steel KP, Richardson GP. Mapping of the a-tectorin gene (TECTA) to mouse chromosome 9 and human chromosome 11: a candidate for human autosomal dominant nonsyndromic deafness. Genomics 1998; 48(1): 46–51

    Article  CAS  PubMed  Google Scholar 

  13. Balciuniene J, Dahl N, Jalonen P, Verhoeven K, Van Camp G, Borg E, Pettersson U, Jazin EE. α-tectorin involvement in hearing disabilities: one gene?two phenotypes. Hum Genet 1999; 105(3): 211–216

    Article  CAS  PubMed  Google Scholar 

  14. Sagong B, Park R, Kim YH, Lee KY, Baek JI, Cho HJ, Cho IJ, Kim UK, Lee SH. Two novel missense mutations in the TECTA gene in Korean families with autosomal dominant nonsyndromic hearing loss. Ann Clin Lab Sci 2010; 40(4): 380–385

    CAS  PubMed  Google Scholar 

  15. Choi BY, Kim J, Chung J, Kim AR, Mun SJ, Kang SI, Lee SH, Kim N, Oh SH. Whole-exome sequencing identifies a novel genotypephenotype correlation in the entactin domain of the known deafness gene TECTA. PLoS ONE 2014; 9(5): e97040

    Article  PubMed  PubMed Central  Google Scholar 

  16. Hildebrand MS, Morín M, Meyer NC, Mayo F, Modamio-Hoybjor S, Mencía A, Olavarrieta L, Morales-Angulo C, Nishimura CJ, Workman H, DeLuca AP, del Castillo I, Taylor KR, Tompkins B, Goodman CW, Schrauwen I, Wesemael MV, Lachlan K, Shearer AE, Braun TA, Huygen PL, Kremer H, Van Camp G, Moreno F, Casavant TL, Smith RJ, Moreno-Pelayo MA. DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss. Hum Mutat 2011; 32(7): 825–834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Alasti F, Sanati MH, Behrouzifard AH, Sadeghi A, de Brouwer AP, Kremer H, Smith RJ, Van Camp G. A novel TECTA mutation confirms the recognizable phenotype among autosomal recessive hearing impairment families. Int J Pediatr Otorhinolaryngol 2008; 72(2): 249–255

    Article  PubMed  Google Scholar 

  18. Meyer NC, Alasti F, Nishimura CJ, Imanirad P, Kahrizi K, Riazalhosseini Y, Malekpour M, Kochakian N, Jamali P, Van Camp G, Smith RJ, Najmabadi H. Identification of three novel TECTA mutations in Iranian families with autosomal recessive nonsyndromic hearing impairment at the DFNB21 locus. Am J Med Genet A 2007; 143A(14): 1623–1629

    Article  CAS  PubMed  Google Scholar 

  19. Fukushima K, Ramesh A, Srisailapathy CR, Ni L, Wayne S, O’Neill ME, Van Camp G, Coucke P, Jain P, Wilcox ER, Smith SD, Kenyon JB, Zbar RI, Smith RJ. An autosomal recessive nonsyndromic form of sensorineural hearing loss maps to 3p-DFNB6. Genome Res 1995; 5(3): 305–308

    Article  CAS  PubMed  Google Scholar 

  20. Naz S, Alasti F, Mowjoodi A, Riazuddin S, Sanati MH, Friedman TB, Griffith AJ, Wilcox ER, Riazuddin S. Distinctive audiometric profile associated with DFNB21 alleles of TECTA. J Med Genet 2003; 40(5): 360–363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Alloisio N, Morlé L, Bozon M, Godet J, Verhoeven K, Van Camp G, Plauchu H, Muller P, Collet L, Lina-Granade G. Mutation in the zonadhesin-like domain of a-tectorin associated with autosomal dominant non-syndromic hearing loss. Eur J Hum Genet 1999; 7(2): 255–258

    Article  CAS  PubMed  Google Scholar 

  22. Kim AR, Chang MY, Koo JW, Oh SH, Choi BY. Novel TECTA mutations identified in stable sensorineural hearing loss and their clinical implications. Audiol Neurootol 2015; 20(1): 17–25

    Article  CAS  PubMed  Google Scholar 

  23. Lu J, Cheng X, Li Y, Zeng L, Zhao Y. Evaluation of individual susceptibility to noise-induced hearing loss in textile workers in China. Arch Environ Occup Health 2005; 60(6): 287–294

    Article  PubMed  Google Scholar 

  24. Zhang X, Liu Y, Zhang L, Yang Z, Yang L, Wang X, Jiang C, Wang Q, Xia Y, Chen Y, Wu O, Zhu Y. Associations of genetic variations in EYA4, GRHL2 and DFNA5 with noise-induced hearing loss in Chinese population: a case-control study. Environ Health 2015; 14: 77

    Article  PubMed  PubMed Central  Google Scholar 

  25. Schönberger J, Wang L, Shin JT, Kim SD, Depreux FF, Zhu H, Zon L, Pizard A, Kim JB, Macrae CA, Mungall AJ, Seidman JG, Seidman CE. Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss. Nat Genet 2005; 37(4): 418–422

    Article  PubMed  Google Scholar 

  26. Hildebrand MS, Coman D, Yang T, Gardner RJ, Rose E, Smith RJ, Bahlo M, Dahl HH. A novel splice site mutation in EYA4 causes DFNA10 hearing loss. Am J Med Genet A 2007; 143A(14): 1599–1604

    Article  CAS  PubMed  Google Scholar 

  27. Choi HS, Kim AR, Kim SH, Choi BY. Identification of a novel truncation mutation of EYA4 in moderate degree hearing loss by targeted exome sequencing. Eur Arch Otorhinolaryngol 2016; 273(5): 1123–1129

    Article  PubMed  Google Scholar 

  28. Kozlowski DJ, Whitfield TT, Hukriede NA, Lam WK, Weinberg ES. The zebrafish dog-eared mutation disrupts eya1, a gene required for cell survival and differentiation in the inner ear and lateral line. Dev Biol 2005; 277(1): 27–41

    Article  CAS  PubMed  Google Scholar 

  29. Wang L, Sewell WF, Kim SD, Shin JT, MacRae CA, Zon LI, Seidman JG, Seidman CE. Eya4 regulation of Na+/K+-ATPase is required for sensory system development in zebrafish. Development 2008; 135(20): 3425–3434

    Article  CAS  PubMed  Google Scholar 

  30. McGuirt WT, Prasad SD, Griffith AJ, Kunst HP, Green GE, Shpargel KB, Runge C, Huybrechts C, Mueller RF, Lynch E, King MC, Brunner HG, Cremers CW, Takanosu M, Li SW, Arita M, Mayne R, Prockop DJ, Van Camp G, Smith RJ. Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13). Nat Genet 1999; 23(4): 413–419

    Article  CAS  PubMed  Google Scholar 

  31. Zhidkova NI, Justice SK, Mayne R. Alternative mRNA processing occurs in the variable region of the pro-a1(XI) and pro-a2(XI) collagen chains. J Biol Chem 1995; 270(16): 9486–9493

    Article  CAS  PubMed  Google Scholar 

  32. Vuoristo MM, Pihlajamaa T, Vandenberg P, Körkkö J, Prockop DJ, Ala-Kokko L. Complete structure of the human COL11A2 gene: the exon sizes and other features indicate the gene has not evolved with genes for other fibriller collagens. Ann N YAcad Sci 1996; 785(1): 343–344

    Article  CAS  Google Scholar 

  33. Kuivaniemi H, Tromp G, Prockop DJ. Mutations in fibrillar collagens (types I, II, III, and XI), fibril-associated collagen (type IX), and network-forming collagen (type X) cause a spectrum of diseases of bone, cartilage, and blood vessels. Hum Mutat 1997; 9(4): 300–315

    Article  CAS  PubMed  Google Scholar 

  34. Prockop DJ. Mutations that alter the primary structure of type I collagen. The perils of a system for generating large structures by the principle of nucleated growth. J Biol Chem 1990; 265(26): 15349–15352

    CAS  PubMed  Google Scholar 

  35. Li Y, Lacerda DA, Warman ML, Beier DR, Yoshioka H, Ninomiya Y, Oxford JT, Morris NP, Andrikopoulos K, Ramirez F, Wardell BB, Lifferth GD, Teuscher C, Woodward SR, Taylor BA, Seegmiller RE, Olsen BR. A fibrillar collagen gene, Col11a1, is essential for skeletal morphogenesis. Cell 1995; 80(3): 423–430

    Article  CAS  PubMed  Google Scholar 

  36. Iwasa Y, Moteki H, Hattori M, Sato R, Nishio SY, Takumi Y, Usami S. Non-ocular Stickler syndrome with a novel mutation in COL11A2 diagnosed by massively parallel sequencing in Japanese hearing loss patients. Ann Otol Rhinol Laryngol 2015; 124(Suppl 1): 111S–117S

    Article  PubMed  Google Scholar 

  37. Chakchouk I, Grati M, Bademci G, Bensaid M, Ma Q, Chakroun A, Foster J 2nd, Yan D, Duman D, Diaz-Horta O, Ghorbel A, Mittal R, Farooq A, Tekin M, Masmoudi S, Liu XZ. Novel mutations confirm that COL11A2 is responsible for autosomal recessive nonsyndromic hearing loss DFNB53. Mol Genet Genomics 2015; 290(4): 1327–1334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Majava M, Hoornaert KP, Bartholdi D, Bouma MC, Bouman K, Carrera M, Devriendt K, Hurst J, Kitsos G, Niedrist D, Petersen MB, Shears D, Stolte-Dijkstra I, Van Hagen JM, Ala-Kokko L, Männikkö M, Mortier GR. A report on 10 new patients with heterozygous mutations in the COL11A1 gene and a review of genotypephenotype correlations in type XI collagenopathies. Am J Med Genet A 2007; 143A(3): 258–264

    Article  CAS  PubMed  Google Scholar 

  39. Vazza G, Picelli S, Bozzato A, Mostacciuolo ML. Identification and characterization of C3orf6, a new conserved human gene mapping to chromosome 3q28. Gene 2003; 314: 113–120

    Article  CAS  PubMed  Google Scholar 

  40. Modamio-Høybjør S, Mencia A, Goodyear R, del Castillo I, Richardson G, Moreno F, Moreno-Pelayo MA. A mutation in CCDC50, a gene encoding an effector of epidermal growth factormediated cell signaling, causes progressive hearing loss. Am J Hum Genet 2007; 80(6): 1076–1089

    Article  PubMed  PubMed Central  Google Scholar 

  41. Pfister M, Thiele H, Van Camp G, Fransen E, Apaydin F, Aydin O, Leistenschneider P, Devoto M, Zenner HP, Blin N, Nurnberg P, Ozkarakas H, Kupka S. A genotype-phenotype correlation with gender-effect for hearing impairment caused by TECTA mutations. Cell Physiol Biochem 2004; 14: 369–376

    Article  CAS  PubMed  Google Scholar 

  42. Collin RW, de Heer AM, Oostrik J, Pauw RJ, Plantinga RF, Huygen PL, Admiraal R, de Brouwer AP, Strom TM, Cremers CW, Kremer H. Mid-frequency DFNA8/12 hearing loss caused by a synonymous TECTA mutation that affects an exonic splice enhancer. Eur J Hum Genet 2008; 16(12): 1430–1436

    Article  CAS  PubMed  Google Scholar 

  43. Verhoeven K, Van Camp G, Govaerts PJ, Balemans W, Schatteman I, Verstreken M, Van Laer L, Smith RJ, Brown MR, Van de Heyning PH, Somers T, Offeciers FE, Willems PJ. A gene for autosomal dominant nonsyndromic hearing loss (DFNA12) maps to chromosome 11q22–24. Am J Hum Genet 1997; 60(5): 1168–1173

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Plantinga RF, de Brouwer AP, Huygen PL, Kunst HP, Kremer H, Cremers CW. A novel TECTA mutation in a Dutch DFNA8/12 family confirms genotype-phenotype correlation. J Assoc Res Otolaryngol 2006; 7(2): 173–181

    Article  PubMed  PubMed Central  Google Scholar 

  45. Iwasaki S, Harada D, Usami S, Nagura M, Takeshita T, Hoshino T. Association of clinical features with mutation of TECTA in a family with autosomal dominant hearing loss. Arch Otolaryngol Head Neck Surg 2002; 128(8): 913–917

    Article  PubMed  Google Scholar 

  46. Wayne S, Robertson NG, DeClau F, Chen N, Verhoeven K, Prasad S, Tranebjärg L, Morton CC, Ryan AF, Van Camp G, Smith RJ. Mutations in the transcriptional activator EYA4 cause late-onset deafness at the DFNA10 locus. Hum Mol Genet 2001; 10(3): 195–200

    Article  CAS  PubMed  Google Scholar 

  47. Makishima T, Madeo AC, Brewer CC, Zalewski CK, Butman JA, Sachdev V, Arai AE, Holbrook BM, Rosing DR, Griffith AJ. Nonsyndromic hearing loss DFNA10 and a novel mutation of EYA4: evidence for correlation of normal cardiac phenotype with truncating mutations of the Eya domain. Am J Med Genet A 2007; 143A(14): 1592–1598

    Article  CAS  PubMed  Google Scholar 

  48. Baek JI, Oh SK, Kim DB, Choi SY, Kim UK, Lee KY, Lee SH. Targeted massive parallel sequencing: the effective detection of novel causative mutations associated with hearing loss in small families. Orphanet J Rare Dis 2012; 7(1): 60

    Article  PubMed  PubMed Central  Google Scholar 

  49. Liu F, Hu J, Xia W, Hao L, Ma J, Ma D, Ma Z. Exome sequencing identifies a mutation in EYA4 as a novel cause of autosomal dominant non-syndromic hearing loss. PLoS ONE 2015; 10(5): e0126602

    Article  PubMed  PubMed Central  Google Scholar 

  50. Harel T, Rabinowitz R, Hendler N, Galil A, Flusser H, Chemke J, Gradstein L, Lifshitz T, Ofir R, Elbedour K, Birk OS. COL11A2 mutation associated with autosomal recessive Weissenbacher-Zweymuller syndrome: molecular and clinical overlap with otospondylomegaepiphyseal dysplasia (OSMED). Am J Med Genet A 2005; 132A(1): 33–35

    Article  PubMed  Google Scholar 

  51. Melkoniemi M, Brunner HG, Manouvrier S, Hennekam R, Superti-Furga A, Kääriäinen H, Pauli RM, van Essen T, Warman ML, Bonaventure J, Miny P, Ala-Kokko L. Autosomal recessive disorder otospondylomegaepiphyseal dysplasia is associated with loss-offunction mutations in the COL11A2 gene. Am J Hum Genet 2000; 66(2): 368–377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Vikkula M, Mariman EC, Lui VC, Zhidkova NI, Tiller GE, Goldring MB, van Beersum SE, de Waal Malefijt MC, van den Hoogen FH, Ropers HH, Miikka Vikkula, R, Cheah KSE, Olsen BR, Warman ML, Brunner HG. Autosomal dominant and recessive osteochondrodysplasias associated with the COL11A2 locus. Cell 1995; 80(3): 431–437

    Article  CAS  PubMed  Google Scholar 

  53. Melkoniemi M, Koillinen H, Männikkö M, Warman ML, Pihlajamaa T, Kääriäinen H, Rautio J, Hukki J, Stofko JA, Cisneros GJ, Krakow D, Cohn DH, Kere J, Ala-Kokko L. Collagen XI sequence variations in nonsyndromic cleft palate, Robin sequence and micrognathia. Eur J Hum Genet 2003; 11(3): 265–270

    Article  CAS  PubMed  Google Scholar 

  54. Vuoristo MM, Pappas JG, Jansen V, Ala-Kokko L. A stop codon mutation in COL11A2 induces exon skipping and leads to nonocular Stickler syndrome. Am J Med Genet A 2004; 130A(2): 160–164

    Article  PubMed  Google Scholar 

  55. Sirko-Osadsa DA, Murray MA, Scott JA, Lavery MA, Warman ML, Robin NH. Stickler syndrome without eye involvement is caused by mutations in COL11A2, the gene encoding the a2(XI) chain of type XI collagen. J Pediatr 1998; 132(2): 368–371

    Article  CAS  PubMed  Google Scholar 

  56. Pihlajamaa T, Prockop DJ, Faber J, Winterpacht A, Zabel B, Giedion A, Wiesbauer P, Spranger J, Ala-Kokko L. Heterozygous glycine substitution in the COL11A2 gene in the original patient with the Weissenbacher-Zweymüller syndrome demonstrates its identity with heterozygous OSMED (nonocular Stickler syndrome). Am J Med Genet 1998; 80(2): 115–120

    Article  CAS  PubMed  Google Scholar 

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  1. Institute of Biomedical Sciences, Fudan University, Shanghai, 200023, China

    Wenjun Xia & Duan Ma

  2. Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, School of Basic Medical Sciences, Fudan University, Shanghai, 200023, China

    Fei Liu & Duan Ma

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Xia, W., Liu, F. & Ma, D. Research progress in pathogenic genes of hereditary non-syndromic mid-frequency deafness. Front. Med. 10, 137–142 (2016). https://doi.org/10.1007/s11684-016-0449-8

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