**4.1.1 Autosomal recessive non-syndromic HL**

Autosomal recessive non-syndromic HL (ARNSHL) was first described in 1846. It is the severest form of congenital HL in which there is a defect in cochlea in nearly all cases. Loci of ARNSHL are designated as the DFNB; DF stands for Deafness and B indicates the autosomal recessive pattern of inheritance. Up to date, 46 genes and nearly 100 loci have been identified for HL (Table 3). Regarding different studies, connexin 26 gene mutations differ depending on geographical place and ethnicity [Zelante et al., 1997; Morell et al., 1998; Mahdieh & Rabbani, 2009]. Here, we discuss the most common genes causing ARNSHL.

#### **4.1.1.1** *GJB2* **and** *GJB6* **genes and connexins**

The first locus of ARNSHL designated as DFNB1 was identified by Guilford and colleagues in 1994. These researches confirmed linkage to chromosome 13q12-q13 in two consanguineous families [Guilford et al., 1994]. More consanguineous families of different ethnic groups were linked to the DFNB1 locus [Morle et al., 2000]. Phenotypic differences were observed within different families which indicated that allelic heterogeneity may be present in the locus DFNB1.

*GJB2* is a small gene encompassing 5.5 Kb. It has two exons encoding a 4.2Kb mRNA and a protein of 226 amino acids. A six repeat of G is located at position 30 to 35 of coding region of *GJB2* gene from which deletion of one G is known as 35delG or 30delG (Figure 1) [Kelley et al., 1998]. 35delG is the most common mutation in the Caucasians and may cause up to 70% of all *GJB2* gene mutations. Profound HL caused by *GJB2* gene mutations is found in 50% of the cases; 30% are severe, 20% moderate and 1-2% are mild cases [Smith & Hone, 2003]. Other *GJB2* mutations have been reported with higher frequencies in some ethnic

Genetics of Hearing Loss 217

Autosomal Recessive

Locus Location Gene references

DFNB15 19p13 *GIPC3* Charizopoulou et al., 2011

DFNB16 15q21-q22 *STRC* Verpy et al., 2001 DFNB18 11p14-15.1 *USH1C* Ouyang et al., 2002 DFNB21 11q *TECTA* Mustapha et al., 1999 DFNB22 16p12.2 *OTOA* Zwaenepoel et al ., 2002 DFNB23 10p11.2-q21 *PCDH15* Ahmed et al, 2003 DFNB24 11q23 *RDX* Khan et al., 2007 DFNB25 4p13 *GRXCR1* Schraders et al., 2010 DFNB28 22q13 *TRIOBP* Riazuddin et al, 2006 DFNB29 21q22 *CLDN14* Wilcox et al., 2001 DFNB30 10p11.1 *MYO3A* Walsh et al., 2002 DFNB31 9q32-q34 *WHRN* Mburu et al., 2003 DFNB32 1p13.3-22.1 *GPSM2* Walsh et al., 2010 DFNB35 14q24.1-24.3 *ESRRB* Collin et al., 2008 DFNB36 1p36.3 *ESPN* Naz et al., 2004 DFNB37 6q13 *MYO6* Ahmed et al., 2003 DFNB39 7q21.1 *HGF* Schultz et al., 2009 DFNB42 3q13.31-q22.3 *ILDR1* Borck et al., 2011 DFNB49 5q12.3-q14.1. *MARVELD2* Riazuddin et al., 2006 DFNB53 6p21.3 *COL11A2* Chen et al., 2005 DFNB59 2q31.1-q31.3 *PJVK* Delmaghani et al., 2006

DFNB61 7q22.1 *SLC26A5* Liu et al., 2003 DFNB63 11q13.2-q13.4 *LRTOMT*/ *COMT2* Ahmed et al., 2008 DFNB66 6p21.2-22.3 *LHFPL5* Shabbir et al., 2006 DFNB72 19p13.3 *GIPC3* Rehman et al., 2011 DFNB73 1p32.3 *BSND* Riazuddin et al., 2009 DFNB74 12q14.2-q15 *MSRB3* Ahmed et al., 2011 DFNB77 18q12-q21 *LOXHD1* Grillet et al., 2009 DFNB79 9q34.3 *TPRN* Rehman et al., 2010 DFNB84 12q21.2 *PTPRQ* Schraders er al., 2010 DFNB91 6p25 *SERPINB6* Sirmaci et al., 2010

DFNB95 19p13 *GIPC3* Charizopoulou et al., 2011

Table 3. Non-syndromic genes responsible for HL up to 2011.

DFNB1 13q12 *GJB2* Kelsell et al., 1997 DFNB2 11q13.5 *MYO7A* Liu et al., 1997 DFNB3 17p11.2 *MYO15A* Wang et al., 1998 DFNB4 7q31 *SLC26A4* Li et al., 1998 DFNB6 3p14-p21 *TMIE* Naz et al, 2002 DFNB7/11 9q13-q21 *TMC1* Kurima et al., 2002 DFNB8/10 21q22 *TMPRSS3* Scott et al., 2001 DFNB9 2p22-p23 *OTOF* Yasunaga et al., 1999 DFNB12 10q21-q22 *CDH23* Bork et al., 2001

groups [Morell et al., 1998; Mahdieh & Rabbani, 2009]. A large number of studies have been reported about *GJB2* mutations including genotype-phenotype correlations, phenotypic variability, de novo mutations, dominant mutations, ethnic-specific distribution of mutations, digenic inheritance and allelic heterogeneity [del Castillo et al., 2002; Smith & Hone, 2003; Mahdieh et al., 2009; 2010b, 2010c]. Also, a modifier gene has been suggested because of intrafamilial phenotypic variability of the cases [Higert et al., 2009a; Mahdieh et al., 2010b].

*GJB2* and *GJB6* genes are about 35 kb apart from each other. *GJB6* gene encodes a protein called Connexin 30 (MIM 604418) which has 261 amino acids. Connexin 30 is produced in different tissues of the body such as the cochlea, brain and thyroid [Grifa et al., 1999]. The importance of this gene was evident when some families had a mutated allele of *GJB2* and the second mutant allele was in the *GJB6* (digenic inheritance) [del Castillo et al., 2002].


groups [Morell et al., 1998; Mahdieh & Rabbani, 2009]. A large number of studies have been reported about *GJB2* mutations including genotype-phenotype correlations, phenotypic variability, de novo mutations, dominant mutations, ethnic-specific distribution of mutations, digenic inheritance and allelic heterogeneity [del Castillo et al., 2002; Smith & Hone, 2003; Mahdieh et al., 2009; 2010b, 2010c]. Also, a modifier gene has been suggested because of intrafamilial phenotypic variability of the cases [Higert et al., 2009a; Mahdieh et

*GJB2* and *GJB6* genes are about 35 kb apart from each other. *GJB6* gene encodes a protein called Connexin 30 (MIM 604418) which has 261 amino acids. Connexin 30 is produced in different tissues of the body such as the cochlea, brain and thyroid [Grifa et al., 1999]. The importance of this gene was evident when some families had a mutated allele of *GJB2* and the second mutant allele was in the *GJB6* (digenic inheritance) [del Castillo et al., 2002].

X-Linked

Autosomal Dominant

Locus Location Gene references

DFNX1 Xq22 *PRPS1* Liu et al., 2010 DFNX2 Xq21.1 *POU3F4* De Kok et al., 1995 DFNX4 Xp22 *SMPX* del Castillo et al., 1996

DFNA1 5q31 DIAPH1 Lynch et al., 1997 DFNA2A 1p34 *KCNQ4* Kubisch et al., 1999 DFNA2B 1p35.1 GJB3 Xia et al., 1998 DFNA3A 13q11-q12 *GJB2* Kelsell et al., 1997 DFNA3B 13q12 *GJB6* Grifa et al., 1999 DFNA4 19q13 *MYH14* Donaudy et al, 2004 DFNA5 7p15 *DFNA5* Van Laer et al., 1998 DFNA6 4p16.3 *WFS1* Bespalova et al., 2001 DFNA9 14q12-q13 *COCH* Robertson et al., 1998 DFNA10 6q22-q23 *EYA4* Wayne et al., 2001 DFNA11 11q12.3-q21 *MYO7A* Liu et al., 1997

DFNA12 11q22-24 *TECTA* Verhoeven et al., 1998 DFNA13 6p21 *COL11A2* McGuirt et al., 1999 DFNA15 5q31 *POU4F3* Vahava et al., 1998 DFNA17 22q *MYH9* Lalwani et al., 2000 DFNA20 17q25 *ACTG1* Zhu et al., 2003, DFNA22 6q13 *MYO6* Melchionda et al., DFNA28 8q22 *GRHL2* Peters et al., 2002 DFNA36 9q13-q21 *TMC1* Kurima et al., 2002 DFNA39 4q21.3 *DSPP* Xiao et al., 2001

DFNA44 3q28-29 *CCDC50* Modamio-Hoybjor et al., 2007

DFNA48 12q13-q14 *MYO1A* Donaudy et al., 2003 DFNA50 7q32.2 *MIR96* Mencia et al., 2009 DFNA51 9q21 *TJP2* Walsh et al., 2010 DFNA64 12q24.31-12q24.32 *SMAC*/*DIABLO* Cheng et al., 2011

al., 2010b].


Table 3. Non-syndromic genes responsible for HL up to 2011.

Genetics of Hearing Loss 219

A few point mutations have also been reported in *GJB6* as the cause of ARNSHL *GJB6* [del Castillo et al., 2005; Pallares-Ruiz et al., 2002]. Later studies determined that *GJB6* mutations in cis state, not in trans, would destroy the *GJB2* expression. Therefore, the digenic hypothesis may not be correct. Four large deletions have been recognized in *GJB6* gene including del(*GJB6*-D13S1830), del(*GJB6*-D13S1854), del(chr13:19,837,344-19, 968,698) and 920 Kb deletion [del Castillo et al., 2002, 2005; Wilch et al., 2010]. The deletions may include more than 10% of DFNB1alleles [Stevenson et al., 2003]. So far, del (*GJB6*-D13S1830) has not been seen in many populations [Mahdieh et al., 2004, 2011]. The del (*GJB6*-D13S1830) and del (*GJB6*-D13S1854) mutations not only truncate the synthesis of *GJB6* gene but also destroy

Connexins encoded by GJ genes are members of transmembrane family proteins that have 20 members in humans [Holms & Steel, 1999]. These proteins were classified in three groups of alpha, beta and gamma proteins. Common nomenclature system is based on molecular weight of proteins e.g. Cx26 and Cx32. Despite the differences in the size and primary amino acid composition, connexins have similar topology. These proteins have four transmembrane domains which are connected by two extracellular and one intracellular loop. The carboxyl and amino terminals are located at the cytoplasmic side. Most cells express more than one type of connexin. Gap junctions show different permeability and conductance which may create channels with specific characteristics. Also, in order to compensate for the decrease in the expression of some of the connexins, other connexins may be produced at an enhanced rate [Kumar & Kilula, 1996]. Hemichannels (connexons) are composed of six connexin subunits and two hemi-channels make the channel forming the gap junctions [Kelley et al., 1998]. The important role of these channels is transportation of potassium ions [Kelley et al., 1998] and glutamate released from hair cells to initiate action potential. Different connexins may be made up of hemi

In 1995, a report showed that 2% of rural individuals in the north coast of Bali, Indonesia were affected with a profound sensorineural non-syndromic HL. Due to high percentage of deaf people in this village a local sign language had been created for communication [Wang

The locus was mapped on chromosome 17p11.2 by whole genome study. *MYO15A* gene has 66 exons and 71097 bp, encoding a 11863 bp transcript [Liang et al., 1999]. Myosin gene was identified by positional and functional cloning approaches [Wang et al., 1998]. Mutations in the gene are responsible for 5% of severe to profound deafness cases in Pakistan [Friedman et al., 2003]. *MYO15A* gene mutations were reported in families from Turkey, Brazil and India [Kalay et al., 2007; Nal et al., 2007; Lezirovitz et al., 2008]. The role of myosin filaments can be traced in a variety of cellular functions including cell motility, muscle contraction, synaptic transmission, cytokenesis, endocytosis, exocytosis and probably in gene expression as a modulator [Craig & Woodhead, 2006; Loikkanen et al., 2009]. As the organism gets more complex, there may be more myosin isoforms found in the organism [Oliver et al., 1999; Friedman et al., 1999]. The heavy chain of XV myosin has 3531 amino acids. There is a unique proline-rich region at the amino terminal of myosin which weighs 140KDa and has no similarity to any of the known proteins. Next to this domain exists a motor domain and a tail domain [Belyantseva et al., 2003]. In addition to the

*GJB2* gene expression.

channels with homomer or heteromer subunits.

**4.1.1.2** *MYO15A* **gene in DFNB3 locus** 

et al., 1998].

Fig. 1. Schematic structure and domains of Connexin 26 protein, Connexon and Gap Junction channel. A) The most common mutations in specific populations (35delG, 167delT, 235delC, R143W and W24X mutations in the Caucasian, Ashkenazi Jewish, Japanese, Ghanian and Indian populations, respectively) are shown. 35delG, W24X, 167delT, 235delC and R143W located on NT, TM1, EC1, TM2 and TM3 domains, respectively. TM1-TM4 denotes transmembrane domains, EC1-2 denotes extracellular domains, IC denotes cytoplasmic domain, NT denotes amino (NH2) terminus and CT denotes carboxyl (COOH) terminus. B) Six connexins can oligomerize to form hemichannels named connexons. Connexons then pass throughout the membrane to make the gap junction channels. Homomeric and heteromeric channels can be formed as connexins selectively interact with each other.

Fig. 1. Schematic structure and domains of Connexin 26 protein, Connexon and Gap

each other.

Junction channel. A) The most common mutations in specific populations (35delG, 167delT, 235delC, R143W and W24X mutations in the Caucasian, Ashkenazi Jewish, Japanese, Ghanian and Indian populations, respectively) are shown. 35delG, W24X, 167delT, 235delC and R143W located on NT, TM1, EC1, TM2 and TM3 domains, respectively. TM1-TM4 denotes transmembrane domains, EC1-2 denotes extracellular domains, IC denotes

cytoplasmic domain, NT denotes amino (NH2) terminus and CT denotes carboxyl (COOH) terminus. B) Six connexins can oligomerize to form hemichannels named connexons. Connexons then pass throughout the membrane to make the gap junction channels. Homomeric and heteromeric channels can be formed as connexins selectively interact with

A few point mutations have also been reported in *GJB6* as the cause of ARNSHL *GJB6* [del Castillo et al., 2005; Pallares-Ruiz et al., 2002]. Later studies determined that *GJB6* mutations in cis state, not in trans, would destroy the *GJB2* expression. Therefore, the digenic hypothesis may not be correct. Four large deletions have been recognized in *GJB6* gene including del(*GJB6*-D13S1830), del(*GJB6*-D13S1854), del(chr13:19,837,344-19, 968,698) and 920 Kb deletion [del Castillo et al., 2002, 2005; Wilch et al., 2010]. The deletions may include more than 10% of DFNB1alleles [Stevenson et al., 2003]. So far, del (*GJB6*-D13S1830) has not been seen in many populations [Mahdieh et al., 2004, 2011]. The del (*GJB6*-D13S1830) and del (*GJB6*-D13S1854) mutations not only truncate the synthesis of *GJB6* gene but also destroy *GJB2* gene expression.

Connexins encoded by GJ genes are members of transmembrane family proteins that have 20 members in humans [Holms & Steel, 1999]. These proteins were classified in three groups of alpha, beta and gamma proteins. Common nomenclature system is based on molecular weight of proteins e.g. Cx26 and Cx32. Despite the differences in the size and primary amino acid composition, connexins have similar topology. These proteins have four transmembrane domains which are connected by two extracellular and one intracellular loop. The carboxyl and amino terminals are located at the cytoplasmic side. Most cells express more than one type of connexin. Gap junctions show different permeability and conductance which may create channels with specific characteristics. Also, in order to compensate for the decrease in the expression of some of the connexins, other connexins may be produced at an enhanced rate [Kumar & Kilula, 1996]. Hemichannels (connexons) are composed of six connexin subunits and two hemi-channels make the channel forming the gap junctions [Kelley et al., 1998]. The important role of these channels is transportation of potassium ions [Kelley et al., 1998] and glutamate released from hair cells to initiate action potential. Different connexins may be made up of hemi channels with homomer or heteromer subunits.

#### **4.1.1.2** *MYO15A* **gene in DFNB3 locus**

In 1995, a report showed that 2% of rural individuals in the north coast of Bali, Indonesia were affected with a profound sensorineural non-syndromic HL. Due to high percentage of deaf people in this village a local sign language had been created for communication [Wang et al., 1998].

The locus was mapped on chromosome 17p11.2 by whole genome study. *MYO15A* gene has 66 exons and 71097 bp, encoding a 11863 bp transcript [Liang et al., 1999]. Myosin gene was identified by positional and functional cloning approaches [Wang et al., 1998]. Mutations in the gene are responsible for 5% of severe to profound deafness cases in Pakistan [Friedman et al., 2003]. *MYO15A* gene mutations were reported in families from Turkey, Brazil and India [Kalay et al., 2007; Nal et al., 2007; Lezirovitz et al., 2008]. The role of myosin filaments can be traced in a variety of cellular functions including cell motility, muscle contraction, synaptic transmission, cytokenesis, endocytosis, exocytosis and probably in gene expression as a modulator [Craig & Woodhead, 2006; Loikkanen et al., 2009]. As the organism gets more complex, there may be more myosin isoforms found in the organism [Oliver et al., 1999; Friedman et al., 1999]. The heavy chain of XV myosin has 3531 amino acids. There is a unique proline-rich region at the amino terminal of myosin which weighs 140KDa and has no similarity to any of the known proteins. Next to this domain exists a motor domain and a tail domain [Belyantseva et al., 2003]. In addition to the

Genetics of Hearing Loss 221

DFNB8/10 locus was separately mapped on chromosome 21q22.3 in two consanguineous Pakistani (DFNB8) and Palestinian families (DFNB10) [Bonné-Tamir et al., 1996; Veske et al., 1996]. Haplotype analysis and sequencing analysis of the families resulted in detection of mutations in *TMPRSS3* [Scott et al., 2001]. The gene belongs to a subfamily of transmembrane serine proteases type III protein [Szabo et al., 2003] expressed in supporting cells of the organ of Corti [Guipponi et al., 2002]. Although, the specific role of *TMPRSS3* protein in growth, development and survival of auditory apparatus has not been found but it activates the epithelial sodium channel (ENaC) in vitro [Guipponi et al., 2002]. The mutated alleles of the gene may inactivate the serine protease catalytic activitiy. Therefore, *TMPRSS3* proteolytic function may be important during the development of inner ear [Guipponi et al.,

*TMPRSS3* gene has 13 exons within 24 Kb, encoding a 2468 bp mRNA which encodes a protein with 454 amino acids [Guipponi et al., 2008]. In 2009, 16 mutations in *TMPRSS3* have been reviwed and reported by a study [Hilgert et al., 2009b]. From 25 studied Turkish families, three had mutations of *TMPRSS3* gene [Wattenhofer et al., 2005; Sahin-Calapoglu et al., 2005]. Mutations of *TMPRSS3* gene account for 1% of hearing loss in Caucasian children with non-syndromic HL [Wattenhofer et al., 2005]. Mutations of *TMPRSS3* gene have been reported in 4 of 290 Pakistani families [Ahmed et al., 2004].

*OTOF* gene contains 48 exons encoding a 1997 amino acid polypeptide called otoferlin which is member of Ferlin family of proteins [Mirghomizadeh et al., 2002]. Ferlin family of proteins have a domain called C2. These proteins contain a transmembrane C-terminal domain [Yasunaga et al., 1999]. C2 domain is a structural domain in some proteins that are

Otoferlin is expressed in the brain and cochlea. This protein plays an important role in releasing neurotransmitters in the auditory nerve cells [Yasunaga et al., 1999]. Mutations of the gene can lead to auditory neuropathy in which the sound from inner ear is not transferred to the brain. Q829X mutation is very common in the Hispanic which is the third cause of ARNSHL [Migliosi et al., 2002]. Mutations of the gene have been found in families of Lebanese origin [Yasunaga et al., 1999]. Varga *et al*. reported 8 mutations in 65 studied families with ARNSHL [Varga et al., 2006]. OTOF mutations have been found in Pakistani families; gene mutations may account for deafness in 2.3% of this population [Choi et al.,

The superfamily of cadherin has about 100 members with a variety of roles in cell adhesion, growth and developmental signaling, maintenance and function of the tissues [Jamora & Fuchs, 2002; Nelson & Nusse, 2004; Gumbiner, 2005; Halbleib & Nelson, 2006]. Cadherin 23 protein has a role in connection of developing stereocilia [Siemens et al., 2004]. In 1996, DFNB12 was mapped to chromosome 10q21-q22 in a consanguineous Syrian family [Chaib et al., 1996]. Usher syndrome type 1 D (USH1D) was also mapped to the same position. Allelic mutations of the *CDH23* gene encoding cadherin 23 cause DFNB12 HL and USH1D [Bolz et al., 2001; Bork et al., 2001]. Missense mutations usually cause DFNB12 HL

involved in directing proteins to the cell membrane [Davletov & Südhof, 1993].

**4.1.1.5** *TMPRSS3* **gene in DFNB8/10 locus** 

**4.1.1.6** *OTOF* **gene in DFNB9 locus** 

**4.1.1.7** *CDH23* **gene in DFNB12 locus** 

2002, 2008].

2009].

sensory cells of cochlear, myosin is expressed in the pituitary gland, neuroendocrine cells, parathyroid and pancreas [Llyod et al., 2001]. It is also found in stereocilia of hair cells [Belyantseva et al., 2003].

#### **4.1.1.3** *SLC26A4* **gene in DFNB4 locus**

DFNB4 locus, located at chromosome 7q31, was first reported to be linked to recessive nonsyndromic deafness in a large Middle-Eastern Druze family. In 1997, the *SLC26A4* (Penderin coding protein) was identified by positional cloning at the pendred syndrome locus (Everett et al. 1997) and was later also shown to be the gene mutated in DFNB4 [Li et al., 1998]. Pendred syndrome was identified in 1896 as neurosensory HL and goiter. HL in Pendred syndrome is the most common cause of deafness due to defect of cochlea such as dilation sac and duct of endolyph and enlarged vestibular duct [Everett et al., 1997].

Mutations of *SLC26A4* gene are the second leading cause of ARNSHL. So far, more than 140 mutations have been reported for Pendred syndrome. Phenotypic spectrum of *SLC26A4* gene mutations varies from Pendred syndrome to nonsyndromic HL. Four mutations are common in northern Europeans i.e L236P, T416P, E384G, IVS8 +1 G> A) [Hilgert et al., 2008]. In a study conducted in Spanish population 27% had homozygous *SLC26A4* mutations [Pera et al., 2008]. Mutations of *SLC26A4* gene have been observed in several ethnic populations [Albert et al., 2006; Hu et al., 2007; Yoon et al., 2008]. The prevalence of *SLC26A4* gene mutation is about 40% in Caucasians of which 24% are bi-allelic [Albert et al., 2006].

*SLC26A4* gene has 21 exons within 57175 bp of DNA sequence. Its transcript is about 5 Kb encoding into a 87KDa protein having 780 amino acids. The gene is expressed in lining cells of endolymph duct as well as non-sensory cells of utricle, saccule, kidney and thyroid. Various models have been reported for the structure of Pendrin protein. New model suggests that pendrin protein is a transmembrane protein traversing fifteen times throughout the membrane [Dossena et al., 2009]. The protein in involved in anion exchange of HCO-, Cl-, I-and OH- ions [Mount & Romero, 2004].

#### **4.1.1.4** *TMC1* **gene in DFNB7/11 locus**

DFNB7 and DFNB11 were determined as the cause of HL on chromosome 9q13-q21 in two Indian and two inbred Israeli families, respectively [Jian et al., 1995]. In 2002, eight different mutations in *TMC1* gene were linked to one DFNA36 family and eleven DFNB7/11 families [Kurima et al., 2002]. More than twenty different point mutations and two deletions have been identified in different families. It seems that c.100C>T mutation includes appromximately 40% of all *TMC1* mutations in Turkey [Hilgert et al., 2008, 2009b]. In a survey of 51 Turkish families, 5 patients had mutations of *TMC1* gene [Hilgert et al., 2008]. Mutations of *TMC1* are responsible for at least 6% of all cases of ARNSHL in northeast and eastern part of Turkey [Kalay et al., 2005]. Three mutations c.100C> T (R34X), c.77611G> A and g.94615A> C have been reported in Iranian families [Hilgert et al., 2009b].

Based on sequence homology studies, eight TMC genes exist in vertebrates. *TMC1* gene has 24 exons and encodes a 3201 nucleotide RNA. It expresses a complete transmembrane protein with six membrane passing domain which has no similarity to proteins of known function. Mouse ortholog transcript (*TMC1*) is expressed in cochlea and vestibular hair cells [Kurima et al., 2002].

sensory cells of cochlear, myosin is expressed in the pituitary gland, neuroendocrine cells, parathyroid and pancreas [Llyod et al., 2001]. It is also found in stereocilia of hair cells

DFNB4 locus, located at chromosome 7q31, was first reported to be linked to recessive nonsyndromic deafness in a large Middle-Eastern Druze family. In 1997, the *SLC26A4* (Penderin coding protein) was identified by positional cloning at the pendred syndrome locus (Everett et al. 1997) and was later also shown to be the gene mutated in DFNB4 [Li et al., 1998]. Pendred syndrome was identified in 1896 as neurosensory HL and goiter. HL in Pendred syndrome is the most common cause of deafness due to defect of cochlea such as

Mutations of *SLC26A4* gene are the second leading cause of ARNSHL. So far, more than 140 mutations have been reported for Pendred syndrome. Phenotypic spectrum of *SLC26A4* gene mutations varies from Pendred syndrome to nonsyndromic HL. Four mutations are common in northern Europeans i.e L236P, T416P, E384G, IVS8 +1 G> A) [Hilgert et al., 2008]. In a study conducted in Spanish population 27% had homozygous *SLC26A4* mutations [Pera et al., 2008]. Mutations of *SLC26A4* gene have been observed in several ethnic populations [Albert et al., 2006; Hu et al., 2007; Yoon et al., 2008]. The prevalence of *SLC26A4* gene mutation is about 40% in Caucasians of which 24% are bi-allelic [Albert et al.,

*SLC26A4* gene has 21 exons within 57175 bp of DNA sequence. Its transcript is about 5 Kb encoding into a 87KDa protein having 780 amino acids. The gene is expressed in lining cells of endolymph duct as well as non-sensory cells of utricle, saccule, kidney and thyroid. Various models have been reported for the structure of Pendrin protein. New model suggests that pendrin protein is a transmembrane protein traversing fifteen times throughout the membrane [Dossena et al., 2009]. The protein in involved in anion exchange

DFNB7 and DFNB11 were determined as the cause of HL on chromosome 9q13-q21 in two Indian and two inbred Israeli families, respectively [Jian et al., 1995]. In 2002, eight different mutations in *TMC1* gene were linked to one DFNA36 family and eleven DFNB7/11 families [Kurima et al., 2002]. More than twenty different point mutations and two deletions have been identified in different families. It seems that c.100C>T mutation includes appromximately 40% of all *TMC1* mutations in Turkey [Hilgert et al., 2008, 2009b]. In a survey of 51 Turkish families, 5 patients had mutations of *TMC1* gene [Hilgert et al., 2008]. Mutations of *TMC1* are responsible for at least 6% of all cases of ARNSHL in northeast and eastern part of Turkey [Kalay et al., 2005]. Three mutations c.100C> T (R34X), c.77611G> A

Based on sequence homology studies, eight TMC genes exist in vertebrates. *TMC1* gene has 24 exons and encodes a 3201 nucleotide RNA. It expresses a complete transmembrane protein with six membrane passing domain which has no similarity to proteins of known function. Mouse ortholog transcript (*TMC1*) is expressed in cochlea and vestibular hair cells

and g.94615A> C have been reported in Iranian families [Hilgert et al., 2009b].

of HCO-, Cl-, I-and OH- ions [Mount & Romero, 2004].

**4.1.1.4** *TMC1* **gene in DFNB7/11 locus** 

[Kurima et al., 2002].

dilation sac and duct of endolyph and enlarged vestibular duct [Everett et al., 1997].

[Belyantseva et al., 2003].

2006].

**4.1.1.3** *SLC26A4* **gene in DFNB4 locus** 
