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

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 mid-frequency 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.

Keywords

hereditary non-syndromic hearing loss / mid-frequency hearing loss / deafness genes

Introduction

With a prevalence of 0.1%, hearing loss is the most common sensory impairment affecting several million people worldwide [ 1]. In China, the prevalence of hearing loss ranges from 1‰‒3‰ [ 2]. The Second National Sample Survey on Disability indicates that people with hearing disability account for 27% of all persons with disabilities [ 3]. Numerous factors, such as genetic and environmental factors, can cause deafness; in particular, genetic factors account for over half of all deafness cases.

Approximately 70% of hereditary hearing loss is non-syndromic hearing loss (NSHL), in which hearing impairment is not associated with any additional clinical phenotypes [ 4]. Monogenic hearing loss can be inherited in various ways. Autosomal recessive non-syndromic hearing loss (ARNSHL) occurs in 80% of cases and is typically pre-lingual, whereas autosomal dominant non-syndromic hearing loss (ADNSHL) accounts for approximately 20% of cases and is often post-lingual [ 5]. A previous study showed that syndromic deafness is frequently associated with chromosome micro-imbalances [ 6], and chromosomal alterations in non-syndromic patients tend to be both small and rare, focusing on specific genes [ 7]. To date, 87 genes for NSHL have been identified (http://hereditaryhearingloss.org/).

Patients were divided into low- (0.25−0.5 kHz), mid- (0.5−2 kHz), high- (2−8 kHz), and total-frequency hearing loss groups, as well as the total deafness group, on the basis of the frequency of hearing loss. Patients with mid-frequency hearing loss show a cookie-bite audiogram [ 8]. Over 80 deafness genes have been reported to date. However, only four genes have been identified to contribute to mid-frequency hearing loss: TECTA, EYA4, COL11A2, and CCDC50. This paper discusses the research progress on the four genes.

TECTA

TECTA is a causative gene of both autosomal recessive (DFNB 21) and autosomal dominant (DFNA8/A12) NSHL [ 9, 10]. TECTA includes 23 exons and encodes a-tectorin, a non-collagenous glycoprotein of the tectorial membrane composed of 2156 amino acids; TECTA is located on chromosome 11q22–24 [ 11]. Moreover, TECTA is one of the major non-collagenous components of the tectorial membrane. The tectorial membrane is an extracellular matrix in the inner ear; this membrane covers the neuro-epithelium of the cochlea and contacts the stereocilia bundles of specialized sensory hair cells. Sound induces the movement of these hair cells relative to the tectorial membrane, deflects the stereocilia, and leads to fluctuations in hair-cell membrane potential, which transduces sound into electrical signals [ 11– 13].

α-tectorin, a major non-collagenous component of the tectorial membrane, exhibits many functional domains: the entactin (ENT)-like domain, four von Willebrand factor-like type D (vWFD) domains in the zonadhesin (ZA) domain, and the zona pellucida (ZP) domain [ 14].

Several mutations related to hearing loss have been detected in humans [ 15, 16]. All inactivating mutations in TECTA cause ARNSHL, whereas missense mutations in TECTA lead to ADNSHL [ 16, 17]. Autosomal recessive mutations in TECTA cause a similar audiometric pattern of moderate-to-severe hearing loss, most significantly involving mid-frequency hearing loss [ 18− 20], and the dominant mutations in TECTA are related to characteristic audiogram configurations, depending on which domain the mutations occur [ 13, 14, 21].

Mutations in TECTA account for 4% of all ADNSHL cases in a number of populations; thus, these mutations are regarded as one of the major causes of ADNSHL [ 22]. Missense mutations in TECTA cause dominant forms of non-syndromic deafness, and a genotype-phenotype correlation has been reported in humans, with mutations in the ZP and ZA domains related to mid- and high-frequency hearing losses, respectively [ 11]. Existing studies generally validate previously observed genotype-phenotype correlations in DFNA8/12, as well as introduce new correlations. Specifically, mutations in the entactin-G1-like domain in the first two vWFD repeats and the TIL2 repeats in the ZA and ZP domains are all associated with mid-frequency hearing loss, whereas mutations in the other regions of the ZA domain result in high-frequency hearing loss [ 16].

EYA4

The eyes absent homolog 4 (EYA4), a causative gene of mid-frequency hearing loss, encodes a 639-amino-acid protein serving as a transcription factor; EYA4 is also associated with the composition organ of Corti [ 23]. EYA4 localizes to the ADNSHL locus DFNA10 on chromosome 6q23. The EYA4 gene is encoded for the EYA4 protein, which acts through its phosphatase activity and plays an important role in eye development and for the continued function of the mature organ of Corti [ 24]. Research has indicated the associations between EYA gene mutations and post-lingual, progressive, and autosomal dominant hearing loss [ 25]. Additionally, several mutations in the EYA4 were found to be associated with progressive hearing loss [ 25, 26].

The EYA4 protein is composed of 639 amino acids with two critical domains, including a highly conserved 271-amino-acid C terminus called eyaHR, alternatively called the eya domain or eya homology domain and a more divergent proline-serine-threonine (PST)-rich transactivation domain at the N terminus. Mutations of this gene are known to cause post-lingual and progressive sensorineural hearing losses, either as non-syndromic (DFNA10) or syndromic hearing loss, depending on the location of the truncation of the mutant protein [ 27].

Studies on zebrafish demonstrated the eya4 expression in the mechanosensory epithelia of the zebrafish otic vesicle, as well as those in neuromasts, which are sensory patches related to the mammalian inner ear [ 28], and previous researchers hypothesized that Eya4 regulated the expression of Na⁺/K⁺-ATPase. Scientists examined the subunit levels in eya4 morphant zebrafish and demonstrated the selective reduction of two subunits. The re-expression of the Na⁺/K⁺-ATPase b2b subunit rescued eya4 deficiency in morphant zebrafish. Overall, these results indicate that Eya4 regulates Na⁺/K⁺-ATPase, thereby providing a mechanism by which human EYA4 mutations cause both hearing loss and heart disease [ 29].

COL11A2

Mutations in COL11A2 cause ADNSHL at the DFNA13 locus [ 30] and ARNHSL at the DFNB53 locus. COL11A2 spans ~28 kb and consists of 66 exons and an alternatively spliced exon in the N terminus [ 31, 32]. This gene encodes one of the two α chains of type XI collagen, a minor fibrillar collagen. COL11A2 is located on chromosome 6, which is very close yet separate from the gene for retinoid X receptor β. Type XI collagen is a heterotrimer; however, the third α chain is a post-translationally modified α1 type II chain. The proteolytic processing of this type XI chain produces PARP, a proline/arginine-rich protein that is an N-terminal domain. The collagen family consists of 19 collagens encoded by at least 32 unique genes [ 33]. The common signature collagen motif is the sequential repetition of the amino acid triplet-Gly-X-Y-, where numerous X- and Y-positions are filled by the ring amino acids proline and hydroxyproline; these amino acids facilitate the intertwining of three collagen polypeptide chains into a triple helix [ 34]. Type XI collagen is a minor collagen accounting for<10% of the total cartilage collagen. This type of collagen functions as a spacer in maintaining the interfibrillar distance and fibril diameter of type II collagen [ 35]. The tectorial membrane (TM) of the mammalian cochlea is a gelatinous sheet-like structure anchored at the inner part to the apex of the interdental cells and lies on top of sensory hair cells where the long rows of outer hair cell stereocilia are anchored. The structural integrity of the TM is crucial for it to acquire its complex mechanical properties associated with the hearing process. The TM is composed of four types of collagens (II, V, IX, and XI), five types of non-collagenous glycoproteins (a-tectorin, b-tectorin, otogelin, otoanchorin, and otolin), glycosaminoglycans (uronic acid and keratan sulfate), and CEACAM16. Several of these protein mutations have been identified in human families and cause syndromic or non-syndromic HL [ 36, 37].

A Dutch family (150 relatives in 5 generations; 49 were studied) with autosomal dominant non-syndromic sensorineural mid-frequency hearing impairment raised an association to the DFNA13 locus. Mutation analysis revealed a missense mutation in the COL11A2 gene.

The gene mutations of this type are also associated with type III Stickler syndrome, otospondylomegaepiphyseal dysplasia (OSMED syndrome), and Weissenbacher-Zweymuller syndrome. Phenotype-genotype comparisons suggest that the different phenotypes are dependent on mutations. As collagen folding begins at the carboxy terminus, where the nucleation domain is located, mutations close to the carboxy terminus generate a more severe phenotype [ 38]. This positional effect of missense mutations is common to other diseases associated with collagen folding.

CCDC50

CCDC50 is a gene encoding a tyrosine-phosphorylated effector of EGF-mediated cell signaling known as “Ymer,” which causes non-syndromic, post-lingual, and progressive sensorineural DFNA44; furthermore, this gene is expressed in the inner ear. Mutations in CCDC50 cause mainly low- to mid-frequency hearing losses. The human gene (Hs.478682) is organized in 12 exons, and two alternative transcripts have been identified. The longer transcript (NM_178335) contains a 1449 nt ORF encoding a protein of 482 amino acids, whereas the shorter variant (NM_174908) without exon 6 encodes a protein of 305 amino acids [ 39].

Ymer is expressed in the inner ear during developmental and postnatal maturation and is associated with microtubule-based structures. Moreover, it may play a role in developing the adult inner ear. Thus, we can assume that the pathogenesis of DFNA44 hearing loss, a post-lingual, progressive form of deafness, results from the destabilization of the cytoskeleton in the PCs and stria vascularis of the adult cochlea [ 40].

This paper mainly introduces the four genes causing mid-frequency hearing loss, namely, TECTA, EYA4, COL11A2, and CCDC50 (Table 1). Through the efforts of scientists, we have gathered further knowledge about these genes. However, the process in which these genes lead to hearing loss remains unknown. Furthermore, increasing deafness genes will be derived with the progress of sequencing and bioinformatics, and the mechanism involved will be investigated.

The genetic causes of hearing loss can be detected through sequence analysis, which helps clinicians and patients to delineate the characteristics of a disease. In addition, hearing loss occurring in early childhood can affect linguistic development; as such, strategies should be developed to determine the genetic alterations among patients for further clinical care of hearing loss.

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

[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

[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）

[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 Genet2015 Oct12. [Epub ahead of print] doi: 10.1111/cge.12683

[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

[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

[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

[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

[9] Mustapha M, Weil D, Chardenoux S, Elias S, El-Zir E, Beckmann JS, Loiselet J, Petit C. An α-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

[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 α-tectorin gene cause autosomal dominant non-syndromic hearing impairment. Nat Genet 1998; 19(1): 60–62

[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

[12] Hughes DC, Legan PK, Steel KP, Richardson GP. Mapping of the α-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

[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

[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

[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 genotype-phenotype correlation in the entactin domain of the known deafness gene TECTA. PLoS ONE 2014; 9(5): e97040

[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

[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

[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

[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

[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

[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 α-tectorin associated with autosomal dominant non-syndromic hearing loss. Eur J Hum Genet 1999; 7(2): 255–258

[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

[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

[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

[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

[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

[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

[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

[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

[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

[31] Zhidkova NI, Justice SK, Mayne R. Alternative mRNA processing occurs in the variable region of the pro-α1(XI) and pro-α2(XI) collagen chains. J Biol Chem 1995; 270(16): 9486–9493

[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 Y Acad Sci 1996; 785(1): 343–344

[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

[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

[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

[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

[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 non-syndromic hearing loss DFNB53. Mol Genet Genomics 2015; 290(4): 1327–1334

[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 genotype-phenotype correlations in type XI collagenopathies. Am J Med Genet A 2007; 143A(3): 258–264

[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

[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 factor-mediated cell signaling, causes progressive hearing loss. Am J Hum Genet 2007; 80(6): 1076–1089

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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-of-function mutations in the COL11A2 gene. Am J Hum Genet 2000; 66(2): 368–377

[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

[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

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

[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 α2(XI) chain of type XI collagen. J Pediatr 1998; 132(2): 368–371

[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

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