Table of Contents Author Guidelines Submit a Manuscript
Scientifica
Volume 2016, Article ID 7576064, 9 pages
http://dx.doi.org/10.1155/2016/7576064
Review Article

Genetics of Nonsyndromic Congenital Hearing Loss

Department of Otorhinolaryngology, Faculty of Medicine, Istanbul Medeniyet University, 34722 Istanbul, Turkey

Received 14 December 2015; Accepted 19 January 2016

Academic Editor: Zhijun Duan

Copyright © 2016 Oguz Kadir Egilmez and M. Tayyar Kalcioglu. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Congenital hearing impairment affects nearly 1 in every 1000 live births and is the most frequent birth defect in developed societies. Hereditary types of hearing loss account for more than 50% of all congenital sensorineural hearing loss cases and are caused by genetic mutations. HL can be either nonsyndromic, which is restricted to the inner ear, or syndromic, a part of multiple anomalies affecting the body. Nonsyndromic HL can be categorised by mode of inheritance, such as autosomal dominant (called DFNA), autosomal recessive (DFNB), mitochondrial, and X-linked (DFN). To date, 125 deafness loci have been reported in the literature: 58 DFNA loci, 63 DFNB loci, and 4 X-linked loci. Mutations in genes that control the adhesion of hair cells, intracellular transport, neurotransmitter release, ionic hemeostasis, and cytoskeleton of hair cells can lead to malfunctions of the cochlea and inner ear. In recent years, with the increase in studies about genes involved in congenital hearing loss, genetic counselling and treatment options have emerged and increased in availability. This paper presents an overview of the currently known genes associated with nonsyndromic congenital hearing loss and mutations in the inner ear.

1. Introduction

Hearing loss (HL) is a common disorder, and congenital hearing impairment affects nearly 1 in every 1000 live births; it is one of the most distressing disorders and the most frequent birth defect in developed societies [1]. Hearing impairment affects speech development, language acquisition, and education in children and, as a result, often leads to decreased opportunities in work life as those with hearing loss move to isolating themselves from society. In the US, it is estimated that the social costs of untreated hearing loss over the course of a lifetime can reach up to 1.1 million for every untreated person [2]. These costs could be decreased by 75 percent with early intervention and treatment [3].

Hereditary hearing loss accounts for almost 50% of all congenital sensorineural hearing loss cases, and it is caused by genetic mutations [4]. Deafness can be the result of a mutation in a single gene or a combination of mutations of different genes; it can also be a result of environmental causes such as trauma, medications, medical problems, and environmental exposure or the result of an association between environmental factors and genetics [5].

HL can be either nonsyndromic, which is restricted to the inner ear, or syndromic, a part of multiple anomalies affecting the body. Nonsyndromic HL can further be categorised by its mode of inheritance. Approximately 20% of nonsyndromic sensorineural hearing loss (NSSHL) is inherited as autosomal dominant, which is also referred to as DFNA; this type of hearing loss is usually delayed onset. Eighty percent of inherited HL is autosomal recessive (DFNB), in which hearing loss is generally congenital, but some forms may emerge later in life. The inheritance of the remaining types of HL is either mitochondrial or X-linked (DFN) (less than 1 percent) [2]. To date, 125 deafness loci have been reported in the literature: 58 DFNA loci, 63 DFNB loci, and 4 X-linked loci (http://hereditaryhearingloss.org/) [6].

Many genes are involved in inner-ear function, and the ear is very sensitive to mutations in genetic loci. This is because the physiology and structure of the inner ear are unique and unlike other anatomical locations. Mutations in genes that control the adhesion of hair cells, intracellular transport, neurotransmitter release, ionic hemeostasis, and cytoskeletons of hair cells can lead to malfunctions of the cochlea and inner ear.

In recent years, with the increase in studies of genes involved in congenital hearing loss, genetic counselling and treatment options have emerged and increased in availability. In diagnostic tests, genes that are common causes of hearing loss, such as GJB2, GJB6, SLC26A4, and OTOF, are frequently involved [7]. The results of these tests can be used when counselling parents about the prognosis of a child’s hearing loss, predicting recurrence in the future offspring and taking into consideration therapeutic options like cochlear implantation [2]. In recent studies, some viral vectors were delivered into the inner ear to replace the normal copy of the gene with the defective gene causing hearing loss. In an animal study, an adenovirus-delivered SLC17A8 (VGLUT-3; vesicular glutamate transporter 3) was found to restore hearing in the mice. In another study, hair cell development and regeneration were induced by delivering the ATOH1 gene [8, 9].

This minireview has presented an overview and described the currently known genes associated with nonsyndromic congenital hearing loss and mutations that cause malfunctional proteins in the inner ear (Table 1).

Table 1: Genes related with nonsyndromic hearing loss.

2. Genes and Proteins Related to Nonsyndromic Hearing Loss

2.1. Adhesion Proteins

The stereocilia of hair cells in the cochlea are linked and interconnected to the tectorial membrane by different adhesion proteins. Hair bundles are stabilized by a set of temporary links such as transient lateral links and ankle links. These links also induce growth and maturation with signalling complexes [10]. In mature hair cells, stereocilia are connected by tectorial attachment crowns, horizontal top connectors, and tip links [2]. To date, several genes related to the linking apparatus have been reported. These are DFNA4 (CEACAM16 (carcinogenic antigen-related cell adhesion molecule 16)) [11], DFNB12 (CDH23 (cadherin 23)) [12], DFNB16 (STRC (stereocilin)) [13], DFNB18 (USH1C (harmonin)) [14, 15], DFNB22 (OTOA (otoancorin)) [16], DFNB23 (PCDH15 (protocadherin 15)) [17], DFNB31 (WHRN (whirlin)) [18], DFNB66/67 (TMHS (tetraspan membrane protein)) [19], and DFNB84 (PTPRQ (tyrosine phospate receptor Q)) [20].

The PTPRQ and TMHS genes, as well as cadherin 23 and protocadherin 15, are parts of the transient lateral link. During development, they prevent the fusion of each stereocilium themselves [2]. In mature hair cells, they become the main parts of the tip link and act as a gate, channelling mechanotransduction and providing stability, taking a central role in auditory function [21].

Whirlin and harmonin regulate the link complexes and serve as scaffolding proteins. Mutations in these proteins cause autosomal recessive type hearing loss, but Sans, which is a third scaffolding protein, is related to a complex syndromic hearing loss, Usher syndrome. The other genes, USH2α and VLGR1b, are also associated with Usher syndrome, and they are part of the stereocilial ankle link [22].

Stereocilin is an extracellular matrix protein that attaches the tallest stereocilia of the outer hair cells to the tectorial membrane [13]. The attachment site of this tectorial membrane is generally formed by CEACAM16. In a similar way, otoancrin also attaches nonsensory cells to the tectorial membrane [16].

2.2. Transport Proteins

In the inner ear, all parts of the myosin family can be used for the transportation of different proteins. When using ATP, these myosin proteins bind to the actin cytockeleton and move forward. Binding sites for carried proteins are on the carboxyl-terminal tails of the transport proteins [23]. The myosins related to hereditary hearing loss are myosin Ia (DFNA48) [24], myosin IIIa (DFNB30) [25], myosin VI (DFNA22/DFNB37) [26, 27], myosin VIIa (DFNA11/DFNB2) [28, 29], nonmuscle myosin heavy chain IX (DFNA17) [30], nonmuscle myosin heavy chain XIV (DFNA4) [31], and myosin XVa (DFNB3) [32]. They all have their own unique functions in the inner-ear hair cells [2].

2.3. Proteins of Synapses

VGLUT3, which is a vesicular glutamate receptor, plays a role in the inner hair cells’ synapses. It is encoded by SLC17A8 in the DFNA25 locus and related to autosomal recessive hearing loss [33]. This protein regulates both the exocytosis and the endocytosis of glutamate. Otoferlin (encoded by OTOF) is a protein that works with myosin VI at the synaptic cleft of the inner hair cell and plays a role in the calcium-dependent fusion of vesicles to the plasma membrane. As a result, glutamate is released and the afferent neuron is excited [34]. In an animal study with OTOF and SLC17A8 knockout mice, there was a reduction in the number of postsynaptic ganglion cells, and it was concluded that these proteins are very important for the preservation and development of normal hearing [35].

2.4. Electromotility

The cochlea is sensitive and selective to sounds delivered by the outer hair cells. This is introduced with a process called electromotility, and a protein called Prestin is thought to be responsible for this [2]. It changes the membrane’s potential and enables the outer hair cell length to be altered. When this occurs, the outer hair cell becomes longer upon hyperpolarization and shorter upon depolarization, so it amplifies its sensitivity to the sound [36]. This protein is encoded as SLC26A5 and was first described by Zheng et al. in 2000 [37]. Mutations in SLC26A5 are the cause of DFNB61 hearing loss [38].

2.5. Cytoskeleton

Mutations in some genes associated with the organisation of the cytoskeleton can cause NSSHL; these are ESPN (espin), RDX (radixin), TRIOBP (trio-binding protein), ACTG1 (γ-actin), TPRN (taperin), DIAPH1 (diaphanous), and SMPX (small muscle protein, X-linked).

The protein espin provides stability to the stereocilial cytoskeleton. A mutation in ESPN can cause DFNB36 and autosomal dominant hearing loss [39]. More steriocillia stability can be achieved with radixin. It links actin filaments to the plasma membrane and presents along the stereocilia. Mutations in RDX can cause DFNB24 and autosomal recessive deafness [40]. γ-actin acts as a building block for the stereocilia of hair cells. These stereocilia are constantly undergoing depolymerisation at the base and actin polymerisation at the tip [41]. Mutations in ACTG1 can cause DFNA20/26 and autosomal dominant hearing loss [42, 43]. Via a constant remodelling process, other proteins are also important for continuity. Diaphanous 1 regulates the reorganisation and polymerisation of actin monomers into polymers. It is encoded as DIAPH1, and mutations in this gene can cause DFNA1 and autosomal dominant hearing loss [44]. The binding and organisation of γ-actin at the base of stereocilia are provided by two isoforms of the TRIOBP gene. Mutations in isoforms that are TRIOBP4 and TRIOBP5 can cause DFNB28 and autosomal recessive type hearing loss [45, 46]. Another protein, taperin, is localised in the base of the stereocilia and associated with DFNB79 [47]. Small muscle protein X-linked, encoded as SMPX (DFN4), has a function in stereocilial development and maintenance in response to the mechanical stress to which stereocilia are subjected [48].

2.6. Ion Homeostasis and Gap Junctions

The cochlea has two types of fluids: perilymph, which is high in sodium and low in potassium, and endolymph, which is high in potassium and low in sodium; this condition makes a highly positive potential (+80 mV) called endocochlear potential. Potassium influx into the hair cells causes depolarisation and, after that, the hair cell repolarises and moves cations back into the endolymph. This ion homeostasis involves tight junction protein 2 (TJP2), tricellulin (MARVELD2/TRIC), claudin 14 (CLDN14), KCNQ4 (KCNQ4), Barttin (BSND), ATP2b2 (ATP2b2/PMCA2), some connexins (GJBs), and pendrin (SLC26A4), and they are all related to hereditary hearing loss [2].

In a mutation of CLDN14 in DFNB29, claudin 14 protein will be absent or dysfunctional, and the space of Nuel that surrounds the basolateral surface of outer hair cells is affected and might change its electrical potential [49]. Similarly, tricellulin, which is encoded as MARVELD2/TRIC, causes DFNB49 when mutated, and it is functioning as tight junction that connects the cells together [45]. Tight junction protein 2, encoded as the TJP2 gene, binds tight junctions to the actin cytoskeleton, and mutations cause DFNA51 and autosomal dominant type hearing loss [50].

KCNQ4 encodes a protein forming a voltage-gated potassium channel. It is expressed in outer hair cells and, if mutated, causes an autosomal dominant type HL, DFNA2a [51]. It aids in the repolarisation of outer hair cells and regulates the sensitivity to sound.

Barttin and pendrin, encoded as BSND and SLC26A4, respectively, are involved in both nonsyndromic and syndromic HL. Pendrin is an anion exchanger and plays a crucial role in the acid-base balance. Both syndromic (Pendred’s syndrome, associated with goiter) and nonsyndromic HL (DFNB4) are related to the extent of the mutation in SLC26A4 [52]. Barttin protein is one of the subunits of the chloride channel. Mostly, mutations in BSND can cause Bartter syndrome, associated with hearing loss and renal abnormalities, but DFNB73 has also been attributed to a mutation in BSND and causing nonsyndromic deafness [53].

A gap junction is a channel extending over two adjacent membranes that enables the exchange of various molecules and ions in the cochlea. These junctions are made up of proteins called connexins. These junctions also play a role in the recycling of potassium ions needed for normal hearing. it is the most common cause of nonsyndromic HL and was the first identified gene is GJB2; it is encoded as connexin 26 (DFNA3a/DFNB1a) [54]. Other connexins related to nonsyndromic HL are connexin 30 (GJB6, DFNA3b/DFNB1b) [55, 56] and connexin 31 (GJB3, DFNA2b/DFNB91) [57, 58].

2.7. Others

There are also extracellular matrix proteins, that is, TECTA (α-tectorin), COL11A2 (type XI collagen α2), and COCH (cochlin), and transcription factors, such as POU4f3 (class 4 POU), POU3f4 (class 3 POU), MIR96 (microRNA 96), GRHL2 (grainy-head-like 2), ESRRB (oestrogen-related receptor β), and EYA4 (eyes absent 4) involved in hereditary HL.

3. Conclusion

This review presents an overview and description of the currently known genes related to hereditary NSSHL. The functions of these genes will be better understood with time, and more genes leading to hearing loss will be discovered soon. With new studies and continued examination, the function of the cochlea will be better understood, and novel molecular and gene therapies for human sensorineural HL will hopefully be developed.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

References

  1. K. R. White, “Early hearing detection and intervention programs: opportunities for genetic services,” American Journal of Medical Genetics A, vol. 130, no. 1, pp. 29–36, 2004. View at Google Scholar · View at Scopus
  2. F. Stelma and M. F. Bhutta, “Non-syndromic hereditary sensorineural hearing loss: review of the genes involved,” The Journal of Laryngology & Otology, vol. 128, no. 1, pp. 13–21, 2014. View at Publisher · View at Google Scholar
  3. R. Keren, M. Helfand, C. Homer, H. McPhillips, and T. A. Lieu, “Projected cost-effectiveness of statewide universal newborn hearing screening,” Pediatrics, vol. 110, no. 5, pp. 855–864, 2002. View at Publisher · View at Google Scholar
  4. R. J. H. Smith, J. F. Bale Jr., and K. R. White, “Sensorineural hearing loss in children,” The Lancet, vol. 365, no. 9462, pp. 879–890, 2005. View at Publisher · View at Google Scholar · View at Scopus
  5. X. M. Ouyang, D. Yan, H. J. Yuan et al., “The genetic bases for non-syndromic hearing loss among Chinese,” Journal of Human Genetics, vol. 54, no. 3, pp. 131–140, 2009. View at Publisher · View at Google Scholar
  6. http://hereditaryhearingloss.org/.
  7. N. Hilgert, R. J. H. Smith, and G. Van Camp, “Forty-six genes causing nonsyndromic hearing impairment: which ones should be analyzed in DNA diagnostics?” Mutation Research/Reviews in Mutation Research, vol. 681, no. 2-3, pp. 189–196, 2009. View at Publisher · View at Google Scholar · View at Scopus
  8. O. Akil, R. P. Seal, K. Burke et al., “Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy,” Neuron, vol. 75, no. 2, pp. 283–293, 2012. View at Publisher · View at Google Scholar · View at Scopus
  9. L. R. Lustig and O. Akil, “Cochlear gene therapy,” Current Opinion in Neurology, vol. 25, no. 1, pp. 57–60, 2012. View at Publisher · View at Google Scholar
  10. R. J. Goodyear, W. Marcotti, C. J. Kros, and G. P. Richardson, “Development and properties of stereociliary link types in hair cells of the mouse cochlea,” Journal of Comparative Neurology, vol. 485, no. 1, pp. 75–85, 2005. View at Publisher · View at Google Scholar · View at Scopus
  11. J. Zheng, K. K. Miller, T. Yang et al., “Carcinoembryonic antigen-related cell adhesion molecule 16 interacts with α-tectorin and is mutated in autosomal dominant hearing loss (DFNA4),” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 10, pp. 4218–4223, 2011. View at Publisher · View at Google Scholar · View at Scopus
  12. J. M. Bork, L. M. Peters, S. Riazuddin et al., “Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23,” The American Journal of Human Genetics, vol. 68, no. 1, pp. 26–37, 2001. View at Publisher · View at Google Scholar · View at Scopus
  13. E. Verpy, S. Masmoudi, I. Zwaenepoel et al., “Mutations in a new gene encoding a protein of the hair bundle cause non-syndromic deafness at the DFNB16 locus,” Nature Genetics, vol. 29, no. 3, pp. 345–349, 2001. View at Publisher · View at Google Scholar · View at Scopus
  14. Z. M. Ahmed, T. N. Smith, S. Riazuddin et al., “Nonsyndromic recessive deafness DFNB18 and usher syndrome type IC are allelic mutations of USHIC,” Human Genetics, vol. 110, no. 6, pp. 527–531, 2002. View at Publisher · View at Google Scholar · View at Scopus
  15. X. M. Ouyang, D. Yan, L. L. Du et al., “Characterization of Usher syndrome type I gene mutations in an Usher syndrome patient population,” Human Genetics, vol. 116, no. 4, pp. 292–299, 2005. View at Publisher · View at Google Scholar · View at Scopus
  16. I. Zwaenepoel, M. Mustapha, M. Leibovici et al., “Otoancorin, an inner ear protein restricted to the interface between the apical surface of sensory epithelia and their overlying acellular gels, is defective in autosomal recessive deafness DFNB22,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 9, pp. 6240–6245, 2002. View at Publisher · View at Google Scholar · View at Scopus
  17. K. Verhoeven, L. Van Laer, K. Kirschhofer et al., “Mutations in the human α-tectorin gene cause autosomal dominant non-syndromic hearing impairment,” Nat Genet, vol. 19, no. 1, pp. 60–62, 1998. View at Publisher · View at Google Scholar
  18. N. G. Robertson, L. Lu, S. Heller et al., “Mutations in a novel cochlear gene cause DFNA9, a human nonsyndromic deafness with vestibular dysfunction,” Nature Genetics, vol. 20, no. 3, pp. 299–303, 1998. View at Publisher · View at Google Scholar
  19. S. Wayne, N. G. Robertson, F. DeClau et al., “Mutations in the transcriptional activator EYA4 cause late-onset deafness at the DFNA10 locus,” Human Molecular Genetics, vol. 10, no. 3, pp. 195–200, 2001. View at Publisher · View at Google Scholar
  20. Z. M. Ahmed, S. Riazuddin, J. Ahmad et al., “PCDH15 is expressed in the neurosensory epithelium of the eye and ear and mutant alleles are responsible for both USH1F and DFNB23,” Human Molecular Genetics, vol. 12, no. 24, pp. 3215–3223, 2003. View at Publisher · View at Google Scholar · View at Scopus
  21. W. T. McGuirt, S. D. Prasad, A. J. Griffith et al., “Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13),” Nature Genetics, vol. 23, no. 4, pp. 413–419, 1999. View at Publisher · View at Google Scholar
  22. O. Vahava, R. Morell, E. D. Lynch et al., “Mutation in transcription factor POU4F3 associated with inherited progressive hearing loss in humans,” Science, vol. 279, no. 5358, pp. 1950–1954, 1998. View at Publisher · View at Google Scholar
  23. P. Mburu, M. Mustapha, A. Varela et al., “Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31,” Nature Genetics, vol. 34, no. 4, pp. 421–428, 2003. View at Publisher · View at Google Scholar · View at Scopus
  24. M. I. Shabbir, Z. M. Ahmed, S. Y. Khan et al., “Mutations of human TMHS cause recessively inherited non-syndromic hearing loss,” Journal of Medical Genetics, vol. 43, no. 8, pp. 634–640, 2006. View at Publisher · View at Google Scholar · View at Scopus
  25. M. Schraders, J. Oostrik, P. L. M. Huygen et al., “Mutations in PTPRQ are a cause of autosomal-recessive nonsyndromic hearing impairment DFNB84 and associated with vestibular dysfunction,” The American Journal of Human Genetics, vol. 86, no. 4, pp. 604–610, 2010. View at Publisher · View at Google Scholar · View at Scopus
  26. P. Kazmierczak, H. Sakaguchi, J. Tokita et al., “Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells,” Nature, vol. 449, no. 7158, pp. 87–91, 2007. View at Publisher · View at Google Scholar · View at Scopus
  27. N. Michalski, V. Michel, A. Bahloul et al., “Molecular characterization of the ankle-link complex in cochlear hair cells and its role in the hair bundle functioning,” The Journal of Neuroscience, vol. 27, no. 24, pp. 6478–6488, 2007. View at Publisher · View at Google Scholar · View at Scopus
  28. L. M. Peters, D. W. Anderson, A. J. Griffith et al., “Mutation of a transcription factor, TFCP2L3, causes progressive autosomal dominant hearing loss, DFNA28,” Human Molecular Genetics, vol. 11, no. 23, pp. 2877–2885, 2002. View at Publisher · View at Google Scholar
  29. L. M. Friedman, A. A. Dror, and K. B. Avraham, “Mouse models to study inner ear development and hereditary hearing loss,” International Journal of Developmental Biology, vol. 51, no. 6-7, pp. 609–631, 2007. View at Publisher · View at Google Scholar · View at Scopus
  30. S. Modamio-Høybjør, M. A. Moreno-Pelayo, A. Mencía et al., “A novel locus for autosomal dominant nonsyndromic hearing loss, DFNA50, maps to chromosome 7q32 between the DFNB17 and DFNB13 deafness loci,” Journal of Medical Genetics, vol. 41, article e14, 2004. View at Publisher · View at Google Scholar
  31. F. Donaudy, A. Ferrara, L. Esposito et al., “Multiple mutations of MYO1A, a cochlear-expressed gene, in sensorineural hearing loss,” The American Journal of Human Genetics, vol. 72, no. 6, pp. 1571–1577, 2003. View at Publisher · View at Google Scholar · View at Scopus
  32. Y. Zhao, F. Zhao, L. Zong et al., “Exome sequencing and linkage analysis identified tenascin-C(TNC) as a novel causative gene in nonsyndromic hearing loss,” PLoS ONE, vol. 8, no. 7, Article ID e69549, 2013. View at Publisher · View at Google Scholar
  33. J. Cheng, Y. Zhu, S. He et al., “Functional mutation of SMAC/DIABLO, encoding a mitochondrial proapoptotic protein, causes human progressive hearing loss DFNA64,” The American Journal of Human Genetics, vol. 89, no. 1, pp. 56–66, 2011. View at Publisher · View at Google Scholar
  34. H. Azaiez, K. T. Booth, F. Bu et al., “TBC1D24 mutation causes autosomal-dominant nonsyndromic hearing loss,” Human Mutation, vol. 35, 7, pp. 819–823, 2014. View at Publisher · View at Google Scholar
  35. L. Zhang, L. Hu, Y. Chai, X. Pang, T. Yang, and H. Wu, “A dominant mutation in the stereocilia-expressing gene TBC1D24 is a probable cause for nonsyndromic hearing impairment,” Human Mutation, vol. 35, no. 7, pp. 814–818, 2014. View at Publisher · View at Google Scholar
  36. G. Xing, J. Yao, B. Wu et al., “Identification of OSBPL2 as a novel candidate gene for progressive nonsyndromic hearing loss by whole-exome sequencing,” Genetics in Medicine, vol. 17, no. 3, pp. 210–218, 2015. View at Publisher · View at Google Scholar
  37. M. Thoenes, U. Zimmermann, I. Ebermann et al., “OSBPL2 encodes a protein of inner and outer hair cell stereocilia and is mutated in autosomal dominant hearing loss (DFNA67),” Orphanet Journal of Rare Diseases, vol. 10, article 15, 2015. View at Publisher · View at Google Scholar
  38. H. Azaiez, A. R. Decker, K. T. Booth et al., “HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice,” PLoS Genetics, vol. 11, no. 3, Article ID e1005137, 2015. View at Publisher · View at Google Scholar
  39. T. Walsh, V. Walsh, S. Vreugde et al., “From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 11, pp. 7518–7523, 2002. View at Publisher · View at Google Scholar · View at Scopus
  40. S. Melchionda, N. Ahituv, L. Bisceglia et al., “MYO6, the human homologue of the gene responsible for deafness in Snell's waltzer mice, is mutated in autosomal dominant nonsyndromic hearing loss,” The American Journal of Human Genetics, vol. 69, no. 3, pp. 635–640, 2001. View at Publisher · View at Google Scholar · View at Scopus
  41. Z. M. Ahmed, R. J. Morell, S. Riazuddin et al., “Mutations of MYO6 are associated with recessive deafness, DFNB37,” The American Journal of Human Genetics, vol. 72, no. 5, pp. 1315–1322, 2003. View at Publisher · View at Google Scholar · View at Scopus
  42. X.-Z. Liu, J. Walsh, P. Mburu et al., “Mutations in the myosin VIIA gene cause non-syndromic recessive deafness,” Nature Genetics, vol. 16, no. 2, pp. 188–190, 1997. View at Publisher · View at Google Scholar · View at Scopus
  43. D. Weil, P. Küssel, S. Blanchard et al., “The autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene,” Nature Genetics, vol. 16, no. 2, pp. 191–193, 1997. View at Publisher · View at Google Scholar · View at Scopus
  44. A. K. Lalwani, J. A. Goldstein, M. J. Kelley, W. Luxford, C. M. Castelein, and A. N. Mhatre, “Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9,” The American Journal of Human Genetics, vol. 67, no. 5, pp. 1121–1128, 2000. View at Publisher · View at Google Scholar
  45. J. M. Schultz, Y. Yang, A. J. Caride et al., “Modification of human hearing loss by plasma-membrane calcium pump PMCA2,” The New England Journal of Medicine, vol. 352, no. 15, pp. 1557–1564, 2005. View at Publisher · View at Google Scholar
  46. F. Donaudy, R. Snoeckx, M. Pfister et al., “Nonmuscle myosin heavy-chain gene MYH14 is expressed in cochlea and mutated in patients affected by autosomal dominant hearing impairment (DFNA4),” The American Journal of Human Genetics, vol. 74, no. 4, pp. 770–776, 2004. View at Publisher · View at Google Scholar · View at Scopus
  47. Y. Liang, A. Wang, I. A. Belyantseva et al., “Characterization of the human and mouse unconventional myosin XV genes responsible for hereditary deafness DFNB3 and shaker 2,” Genomics, vol. 61, no. 3, pp. 243–258, 1999. View at Publisher · View at Google Scholar · View at Scopus
  48. J. Ruel, S. Emery, R. Nouvian et al., “Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice,” The American Journal of Human Genetics, vol. 83, no. 2, pp. 278–292, 2008. View at Publisher · View at Google Scholar · View at Scopus
  49. M. Mustapha, D. Weil, S. Chardenoux et al., “An α-tectorin gene defect causes a newly identified autosomal recessive form of sensorineural pre-lingual non-syndromic deafness, DFNB21,” Human Molecular Genetics, vol. 8, no. 3, pp. 409–412, 1999. View at Publisher · View at Google Scholar
  50. S. Yasunaga, M. Grati, M. Cohen-Salmon et al., “A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness,” Nature Genetics, vol. 21, no. 4, pp. 363–369, 1999. View at Publisher · View at Google Scholar · View at Scopus
  51. R. P. Seal, O. Akil, E. Yi et al., “Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3,” Neuron, vol. 57, no. 2, pp. 263–275, 2008. View at Publisher · View at Google Scholar · View at Scopus
  52. W. E. Brownell, C. R. Bader, D. Bertrand, and Y. de Ribaupierre, “Evoked mechanical responses of isolated cochlear outer hair cells,” Science, vol. 227, no. 4683, pp. 194–196, 1985. View at Publisher · View at Google Scholar · View at Scopus
  53. L. Zheng, G. Sekerková, K. Vranich, L. G. Tilney, E. Mugnaini, and J. R. Bartles, “The deaf jerker mouse has a mutation in the gene encoding the espin actin-bundling proteins of hair cell stereocilia and lacks espins,” Cell, vol. 102, no. 3, pp. 377–385, 2000. View at Publisher · View at Google Scholar · View at Scopus
  54. X. Z. Liu, X. M. Ouyang, X. J. Xia et al., “Prestin, a cochlear motor protein, is defective in non-syndromic hearing loss,” Human Molecular Genetics, vol. 12, no. 10, pp. 1155–1162, 2003. View at Publisher · View at Google Scholar · View at Scopus
  55. S. Naz, A. J. Griffith, S. Riazuddin et al., “Mutations of ESPN cause autosomal recessive deafness and vestibular dysfunction,” Journal of Medical Genetics, vol. 41, no. 8, pp. 591–595, 2004. View at Publisher · View at Google Scholar · View at Scopus
  56. S. Y. Khan, Z. M. Ahmed, M. I. Shabbir et al., “Mutations of the RDX gene cause nonsyndromic hearing loss at the DFNB24 locus,” Human Mutation, vol. 28, no. 5, pp. 417–423, 2007. View at Publisher · View at Google Scholar · View at Scopus
  57. A. K. Rzadzinska, M. E. Schneider, C. Davies, G. P. Riordan, and B. Kachar, “An actin molecular treadmill and myosins maintain stereocilia functional architecture and self-renewal,” The Journal of Cell Biology, vol. 164, no. 6, pp. 887–897, 2004. View at Publisher · View at Google Scholar · View at Scopus
  58. M. Ansar, M. A. Din, M. Arshad et al., “A novel autosomal recessive non-syndromic deafness locus (DFNB35) maps to 14q24.1–14q24.3 in large consanguineous kindred from Pakistan,” European Journal of Human Genetics, vol. 11, no. 1, pp. 77–80, 2003. View at Publisher · View at Google Scholar
  59. E. van Wijk, E. Krieger, M. H. Kemperman et al., “A mutation in the gamma actin 1 (ACTG1) gene causes autosomal dominant hearing loss (DFNA20/26),” Journal of Medical Genetics, vol. 40, no. 12, pp. 879–884, 2003. View at Publisher · View at Google Scholar · View at Scopus
  60. S. Riazuddin, S. Anwar, M. Fischer et al., “Molecular basis of DFNB73: mutations of BSND can cause nonsyndromic deafness or Bartter syndrome,” The American Journal of Human Genetics, vol. 85, no. 2, pp. 273–280, 2009. View at Publisher · View at Google Scholar · View at Scopus
  61. W. Chen, K. Kahrizi, N. C. Meyer et al., “Mutation of COL11A2 causes autosomal recessive non-syndromic hearing loss at the DFNB53 locus,” Journal of Medical Genetics, vol. 42, article e61, 2005. View at Publisher · View at Google Scholar
  62. M. Zhu, T. Yang, S. Wei et al., “Mutations in the γ-actin gene (ACTG1) are associated with dominant progressive deafness (DFNA20/26),” The American Journal of Human Genetics, vol. 73, no. 5, pp. 1082–1091, 2003. View at Publisher · View at Google Scholar · View at Scopus
  63. E. D. Lynch, M. K. Lee, J. E. Morrow, P. L. Welcsh, P. E. León, and M.-C. King, “Nonsyndromic deafness DFNA1 associated with mutation of a human homolog of the Drosophila gene diaphanous,” Science, vol. 278, no. 5341, pp. 1315–1318, 1997. View at Publisher · View at Google Scholar · View at Scopus
  64. S. Riazuddin, S. N. Khan, Z. M. Ahmed et al., “Mutations in TRIOBP, which encodes a putative cytoskeletal-organizing protein, are associated with nonsyndromic recessive deafness,” The American Journal of Human Genetics, vol. 78, no. 1, pp. 137–143, 2006. View at Publisher · View at Google Scholar · View at Scopus
  65. S. Y. Khan, S. Riazuddin, M. Shahzad et al., “DFNB79: reincarnation of a nonsyndromic deafness locus on chromosome 9q34.3,” European Journal of Human Genetics, vol. 18, no. 1, pp. 125–129, 2010. View at Publisher · View at Google Scholar
  66. H. Shahin, T. Walsh, T. Sobe et al., “Mutations in a novel isoform of TRIOBP that encodes a filamentous-actin binding protein are responsible for DFNB28 recessive nonsyndromic hearing loss,” The American Journal of Human Genetics, vol. 78, no. 1, pp. 144–152, 2006. View at Publisher · View at Google Scholar · View at Scopus
  67. A. U. Rehman, R. J. Morell, I. A. Belyantseva et al., “Targeted capture and next-generation sequencing identifies C9orf75, encoding taperin, as the mutated gene in nonsyndromic deafness DFNB79,” The American Journal of Human Genetics, vol. 86, no. 3, pp. 378–388, 2010. View at Publisher · View at Google Scholar · View at Scopus
  68. I. Schrauwen, S. Helfmann, A. Inagaki et al., “A mutation in CABP2, expressed in cochlear hair cells, causes autosomal-recessive hearing impairment,” The American Journal of Human Genetics, vol. 91, no. 4, pp. 636–645, 2012. View at Publisher · View at Google Scholar
  69. M. Simon, E. M. Richard, X. Wang et al., “Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase, cause nonsyndromic deafness and Leigh syndrome,” PLoS Genetics, vol. 11, no. 3, Article ID e1005097, 2015. View at Publisher · View at Google Scholar
  70. G. Mujtaba, J. M. Schultz, A. Imtiaz, R. J. Morell, T. B. Friedman, and S. Naz, “A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss,” Journal of Medical Genetics, vol. 52, no. 8, pp. 548–552, 2015. View at Publisher · View at Google Scholar
  71. S. Delmaghani, A. Aghaie, N. Michalski, C. Bonnet, D. Weil, and C. Petit, “Defect in the gene encoding the EAR/EPTP domain-containing protein TSPEAR causes DFNB98 profound deafness,” Human Molecular Genetics, vol. 21, 17, pp. 3835–3844, 2012. View at Publisher · View at Google Scholar
  72. J. Li, X. Zhao, Q. Xin et al., “Whole-exome sequencing identifies a variant in TMEM132E causing autosomal-recessive nonsyndromic hearing loss DFNB99,” Human Mutation, vol. 36, no. 1, pp. 98–105, 2015. View at Publisher · View at Google Scholar
  73. A. Imtiaz, D. C. Kohrman, and S. Naz, “A frameshift mutation in GRXCR2 causes recessively inherited hearing loss,” Human Mutation, vol. 35, no. 5, pp. 618–624, 2014. View at Publisher · View at Google Scholar
  74. A. Behlouli, C. Bonnet, S. Abdi et al., “EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness,” Orphanet Journal of Rare Diseases, vol. 9, article 55, 2014. View at Publisher · View at Google Scholar
  75. C. Z. Seco, A. M. M. Oonk, M. Domínguez-Ruiz et al., “Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5,” European Journal of Human Genetics, vol. 23, no. 2, pp. 189–194, 2015. View at Publisher · View at Google Scholar
  76. O. Diaz-Horta, A. Subasioglu-Uzak, M. Grati et al., “FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing,” Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 27, pp. 9864–9868, 2014. View at Publisher · View at Google Scholar
  77. D. Weil, A. El-Amraoui, S. Masmoudi et al., “Usher syndrome type I G (USH1G) is caused by mutations in the gene encoding SANS, a protein that associates with the USH1C protein, harmonin,” Human Molecular Genetics, vol. 12, no. 5, pp. 463–471, 2003. View at Publisher · View at Google Scholar
  78. S. Pieke-Dahl, C. G. Möller, P. M. Kelley et al., “Genetic heterogeneity of Usher syndrome type II: localisation to chromosome 5q,” Journal of Medical Genetics, vol. 37, no. 4, pp. 256–262, 2000. View at Publisher · View at Google Scholar
  79. H. Yagi, H. Tokano, M. Maeda et al., “Vlgr1 is required for proper stereocilia maturation of cochlear hair cells,” Genes to Cells, vol. 12, no. 2, pp. 235–250, 2007. View at Publisher · View at Google Scholar
  80. X. Liu, D. Han, J. Li et al., “Loss-of-function mutations in the PRPS1 gene cause a type of nonsyndromic X-linked sensorineural deafness, DFN2,” The American Journal of Human Genetics, vol. 86, no. 1, pp. 65–71, 2010. View at Publisher · View at Google Scholar
  81. Y. J. de Kok, S. M. van der Maarel, M. Bitner-Glindzicz et al., “Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4,” Science, vol. 267, no. 5198, pp. 685–688, 1995. View at Publisher · View at Google Scholar
  82. D. Patzak, O. Zhuchenko, C.-C. Lee, and M. Wehnert, “Identification, mapping, and genomic structure of a novel X-chromosomal human gene (SMPX) encoding a small muscular protein,” Human Genetics, vol. 105, no. 5, pp. 506–512, 1999. View at Publisher · View at Google Scholar · View at Scopus
  83. S. Rost, E. Bach, C. Neuner et al., “Novel form of X-linked nonsyndromic hearing loss with cochlear malformation caused by a mutation in the type IV collagen gene COL4A6,” European Journal of Human Genetics, vol. 22, no. 2, pp. 208–215, 2014. View at Publisher · View at Google Scholar