# Genetics of Nonsyndromic Congenital Hearing Loss

Authors: Oguz Kadir Egilmez; M. Tayyar Kalcioglu
Journal: Scientifica
 (2016)

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## 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.


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## Body

## 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 asGJB2,GJB6,SLC26A4, andOTOF, 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-deliveredSLC17A8 (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 theATOH1 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 (Table1).Table 1
Genes related with nonsyndromic hearing loss.
Locus
Gene
Chromosomal localization
Type of inheritance
Protein
Function
Reference
DFNA1
DIAPH1
5q31
AD
Diaphanous 1
Actin polymerisation (cytoskeleton)
[44]
DFNA2A
KCNQ4
1p34
AD
KCNQ4
Voltage-gated K+ channel (ion haemostasis)
[51]
DFNA2B
GJB3 (Cx31)
1p34
AD
Connexin 31
Gap junction (ion haemostasis)
[57]
DFNA3A
GJB2 (Cx26)
13q12
AD
Connexin 26
Gap junction (ion haemostasis)
[54]
DFNA3B
GJB6 (Cx30)
13q12
AD
Connexin 30
Gap junction (ion haemostasis)
[55]
DFNA4
MYH14
19q13
AD
Nonmuscle myosin heavy chain XIV
Transport
[31]
DFNA4
CAECAM16
19q13
AD
Carcinogenic antigen-related cell adhesion molecule 16
TM attachment crown (adhesion)
[11]
DFNA8/12
TECTA
11q22-24
AD
A-tectorin
Stability and structure of TM (ECM)
[28]
DFNA9
COCH
14q12-q13
AD
Cochlin
Structure of spiral limbus
[30]
DFNA10
EYA4
6q22-q23
AD
Eyes absent 4
Regulation of transcription (transcription factor)
[42]
DFNA11
MYO7A
11q12.3-q21
AD
Myosin VIIa
Transport
[43]
DFNA13
COLL11A2
6p21
AD
Type XI collagenα2
Stability and structure of TM (ECM)
[26]
DFNA15
POU3F4
5q31
AD
Class 3 POU
Regulation of transcription (transcription factor)
[33]
DFNA17
MYH9
22q
AD
Nonmuscle myosin heavy chain IX
Transport
[24]
DFNA20/26
ACTG1
17q25
AD
γ-actin
Building cytoskeleton (cytoskeleton)
[50, 56]
DFNA22
MYO6
6q13
AD
Myosin VI
Regulation of exocytosis, anchoring stereocilia (cytoskeleton)
[29]
DFNA25
SLC17A8
12q21-24
AD
VGLUT-3
Regulation of exocytosis and endocytosis of glutamate (transport)
[32]
DFNA28
TFCP2L3
8q22
AD
Transcription factor CP2-like 3
Regulation of transcription (transcription factor)
[52]
DFNA48
MYO1A
12q13-q14
AD
Myosin Ia
Transport
[34]
DFNA50
MIR96
7q32
AD
MicroRNA96
Regulation of transcription (transcription factor)
[12]
DFNA51
TJP2
AD
Tight junction protein 2
Cell cycle signaling, binding tight junctions to membrane
[13]
DFNA56
TNC
9q31.3-q34.3
AD
Tenascin-C
Stability and structure of TM (ECM)
[14]
DFNA64
SMAC/DIABLO
12q24.31-12q24.32
AD
Second Mitochondria-Derived Activator of Caspase/Direct Inhibitor of Apoptosis protein Binding protein with a low pI
Cell cycle signaling
[15]
DFNA65
TBC1D24
16p13.3
AD
Tbc1 domain family, member 24
Encoding a GTPase-activating protein expressed in the cochlea
[16, 17]
DFNA67
OSBPL2
20q13.2-q13.33
AD
Oxysterol-binding Protein-like Protein 2
Intracellular transport of lipids, particularly oxysterol (transport)
[40, 45]
HOMER2
15q25.2
AD
Homer, drosophila, homolog of 2
Negative regulator of T cell activation
[46]
DFNB1A
GJB2 (Cx26)
13q11-q12
AR
Connexin 26
Gap junction (ion haemostasis)
[13]
DFNB1B
GJB6 (Cx30)
13q12
AR
Connexin 30
Gap junction (ion haemostasis)
[49]
DFNB2
MYO7A
11q
AR
Myosin VIIa
Transport
[25, 43]
DFNB3
MYO15A
17p11.2
AR
Myosin Xva
Transport
[18]
DFNB4
SLC26A4
7q31
AR
Pendrin
Acid-base balance of endolymph (ion haemostasis)
[39]
DFNB9
OTOF
2p23-p22
AR
Otoferlin
Fusion of synaptic vesicles with Ca+2 (transport)
[38]
DFNB12
CDH23
10q21-q22
AR
Cadherin 23
Lateral and tip link (adhesion)
[19]
Modifier of DNFB12
ATP2b2/PMCA2
1p32.3
AR
ATP2b2
ATP dependent Ca+2 pump
[53]
DFNB16
STRC
15q15
AR
Stereocilin
TM attachment links (adhesion)
[20]
DFNB18
USH1C
11p15.1
AR
Harmonin
Scaffolding protein (adhesion)
[48, 58]
DFNB21
TECTA
11q22-q24
AR
α-tectorin
Stability and structure of TM (ECM)
[10]
DFNB22
OTOA
16p12.2
AR
Otoancorin
TM attachment to nonsensroy cells (adhesion)
[21]
DFNB23
PCDH15
10q21-q22
AR
Protocadherin 15
Lateral and tip link (adhesion)
[22]
DFNB24
RDX
11q23
AR
Radixin
Actin binding to plasma membrane (cytoskeleton)
[23]
DFNB28
TRIOBP
22q13.1
AR
Trio-binding protein
Actin binding and organisation (cytoskeleton)
[27, 35]
DFNB29
CLDN14
21q22.3
AR
Claudin 14
Tight junction (ion haemostasis)
[36]
DFNB30
MYO3A
10p11.1
AR
Myosin IIIa
Transport
[37]
DFNB31
WHRN
9q32-q34
AR
Whirlin
Scaffolding protein (adhesion)
[41]
DFNB35
ESRRB
14q21.1-q24.3
AR
Oestrogen-related receptorβ
Regulation of transcription (transcription factor)
[47]
DFNB36
ESPN
1p36.3-p36.1
AR
Espin
Actin crosslinking and bundling (cytoskeleton)
[59]
DFNB37
MYO6
6q13
AR
Myosin VI
Regulation of exocytosis, stereocilia anchoring (transport)
[60]
DFNB49
TRIC
5q12.3-q14.1
AR
Tricellulin
Tight junction (ion haemostasis)
[53]
DFNB53
COL11A2
6p21.3
AR
Type XI collagenα2
Stability and structure of TM (ECM)
[61]
DFNB61
SLC26A5
AR
Prestin
Electromotility
[62]
DFNB67
TMHS
6p21.3
AR
Tetraspan membrane protein
Transient link (adhesion)
[63]
DFNB73
BSND
AR
Barttin
K+ channel maturation and trafficking (ion haemostasis)
[64]
DFNB79
TPRN
9q34.3
AR
Taperin
Actin regulation (cytoskeleton)
[65]
DFNB84
PTPRQ
12q21.31-q21.2
AR
Protein tyrosine phosphate receptor Q
Transient link (adhesion)
[66]
DFNB91
GJB3
6p25
AR
Connexin 31
Gap junction (ion haemostasis)
[67]
DFNB93
CABP2
11q13.2
AR
Calcium-binding protein 2
(ion haemostasis)
[68]
DFNB94
NARS2
11q14.1
AR
Asparaginyl-tRNA synthetase 2
(transport)
[69]
DFNB97
MET
7q31.2
AR
MET protooncogene
Cell-surface receptor for hepatocyte growth factor (adhesion)
[70]
DFNB98
TSPEAR
21q22.3
AR
Thrombospondin-type laminin g domain and ear repeats
Cell permeabilization (transport)
[71]
DFNB99
TMEM132E
17q12
AR
Transmembrane protein 132e
Extracellular receptor
[72]
DFNB101
GRXCR2
5q32
AR
Glutaredoxin, cysteine-rich 2
Organisation of stereocilia (adhesion)
[73]
DFNB102
EPS8
12p12.3
AR
Epidermal growth factor receptor pathway substrate 8
Regulating Rac-specific GEF activity (transcription factor)
[74]
DFNB103
CLIC5
6p21.1
AR
Chloride intracellular channel 5
(ion haemostasis)
[75]
FAM65B
6p22.3
AR
Family with sequence similarity 65, member b
(Cytoskleton)
[76]
Usher syndrome
SANS/USH1G
17q24-25
AR
SANS
Scaffolding protein (adhesion)
[77]
Usher syndrome
USH2A
1q41
AR
Usherin
Ankle link (adhesion)
[78]
Usher syndrome
VLGR1B
AR
Very large G protein-coupled receptor 1
Ankle link (adhesion)
[79]
DFN2
PRPS1
Xq22.3
X-linked
Phosphoribosylpyrophosphate synthetase 1
Purine and pyrimidine biosynthesis
[80]
DFN3
POU3F4
Xq21
X-linked
Class 3 POU
Regulation of transcription (transcription factor)
[81]
DFN6
SMPX
Xp21.2
X-linked
Small muscle protein X-linked
Stereocilial development and maintenance (cytoskeleton)
[82]
DFNX6
COL4A6
Xq22.3
X-linked
Collagen, type IV, alpha-6
Stability and structure of TM (ECM)
[83]
DFNA = nonsyndromic deafness, autosomal dominant; DFNB = nonsyndromic deafness, autosomal recessive; AD = autosomal dominant; AR = autosomal recessive; TM = tectorial membrane; ECM = extracellular matrix; Ca+2 = calcium ion; K+ = potassium ion.


## 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].ThePTPRQ andTMHS 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 andVLGR1b, 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 byCEACAM16. 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 bySLC17A8 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 byOTOF) 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 withOTOF andSLC17A8 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 asSLC26A5 and was first described by Zheng et al. in 2000 [37]. Mutations inSLC26A5 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 areESPN (espin),RDX (radixin),TRIOBP (trio-binding protein),ACTG1 (γ-actin),TPRN (taperin),DIAPH1 (diaphanous), andSMPX (small muscle protein, X-linked).The protein espin provides stability to the stereocilial cytoskeleton. A mutation inESPN 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 inRDX 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 inACTG1 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 asDIAPH1, 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 theTRIOBP gene. Mutations in isoforms that areTRIOBP4 andTRIOBP5 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 asSMPX (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 ofCLDN14 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 asMARVELD2/TRIC, causes DFNB49 when mutated, and it is functioning as tight junction that connects the cells together [45]. Tight junction protein 2, encoded as theTJP2 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 asBSND andSLC26A4, 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 inSLC26A4 [52]. Barttin protein is one of the subunits of the chloride channel. Mostly, mutations inBSND can cause Bartter syndrome, associated with hearing loss and renal abnormalities, but DFNB73 has also been attributed to a mutation inBSND 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 isGJB2; 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), andCOCH (cochlin), and transcription factors, such asPOU4f3 (class 4 POU),POU3f4 (class 3 POU),MIR96 (microRNA 96),GRHL2 (grainy-head-like 2),ESRRB (oestrogen-related receptor β), andEYA4 (eyes absent 4) involved in hereditary HL.


## 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].ThePTPRQ andTMHS 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 andVLGR1b, 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 byCEACAM16. 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 bySLC17A8 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 byOTOF) 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 withOTOF andSLC17A8 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 asSLC26A5 and was first described by Zheng et al. in 2000 [37]. Mutations inSLC26A5 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 areESPN (espin),RDX (radixin),TRIOBP (trio-binding protein),ACTG1 (γ-actin),TPRN (taperin),DIAPH1 (diaphanous), andSMPX (small muscle protein, X-linked).The protein espin provides stability to the stereocilial cytoskeleton. A mutation inESPN 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 inRDX 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 inACTG1 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 asDIAPH1, 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 theTRIOBP gene. Mutations in isoforms that areTRIOBP4 andTRIOBP5 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 asSMPX (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 ofCLDN14 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 asMARVELD2/TRIC, causes DFNB49 when mutated, and it is functioning as tight junction that connects the cells together [45]. Tight junction protein 2, encoded as theTJP2 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 asBSND andSLC26A4, 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 inSLC26A4 [52]. Barttin protein is one of the subunits of the chloride channel. Mostly, mutations inBSND can cause Bartter syndrome, associated with hearing loss and renal abnormalities, but DFNB73 has also been attributed to a mutation inBSND 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 isGJB2; 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), andCOCH (cochlin), and transcription factors, such asPOU4f3 (class 4 POU),POU3f4 (class 3 POU),MIR96 (microRNA 96),GRHL2 (grainy-head-like 2),ESRRB (oestrogen-related receptor β), andEYA4 (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.



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*Source: 7576064-2016-02-18.xml*