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

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., 2002, 2008].

*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].

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

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

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., 2009].

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

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

Genetics of Hearing Loss 223

secretion into the endolymph by strial marginal cells. Ten missense mutations, two small deletions and one splice mutation in *KCNQ4* have been reported so far. It is believed that a dominant-negative effect of the missense mutations in this gene lead to interference of the mutant protein with the normal channel subunit, affecting the pore structure of the channels. Therefore, hearing loss with a lower age of onset is observed at all frequencies [Coucke et al., 1999; Akita et al., 2001]. Deletion mutations which have a haploinsufficiency effect lead to a milder HL with an older age of onset at high frequencies [Coucke et al., 1999;

The DFNA9 causative gene, *COCH* located on 14q12-q13, consists of 11exons and encodes a 550 amino acid extracellular matrix protein named cochlin. This protein has several domains including two von Willebrand factor A-like domains (vWFA1 and 2) and a LCCL domain (a region homologous to a domain in factor C of Limulus). To date, eleven missense mutations and one small deletion in *COCH* gene have been reported. Most of the missense mutations are located within exon 4 and 5 which encode the LCCL domain (Figure 2) [Robertson et al.,

Fig. 2. Schematic structure of cochlin and distribution of the mutations along its domains. The NT signal peptide is followed by a LCCL domain and two vWF domains. S indicates several cysteine residues, NT denotes amino (NH2) terminus and CT denotes carboxyl

There are fewer X-linked forms of HL (DFNX) than ARNSHL and ADNSHL. X-linked form of deafness has been reported as prelingual or progressive in different families. Five loci and three genes (POU3F4, *SMPX* and *PRPS1*) have been reported for X-linked HL

To date, only one locus has been linked to chromosome Y (DFNY1) that was found in a very large Chinese family (seven generations) [Wang et al., 2004]. They reported that the ages of onset for the patrilineal relatives were from 7 to 27 years. *PCDH11Y*, encoding a

protocadherin, was suggested to be the causality [Wang et al., 2004].

Akita et al., 2001].

1998; Collin et al., 2006].

(COOH) terminus.

**4.1.3 X and Y linked HL** 

(http://hereditaryhearingloss.org/).

**4.1.2.3** *COCH* **gene and its protein** 

but nonsense and premature stop codon mutations cause Usher syndrome type 1D although this relationship is not definite. No single gene mutation is common in this gene [Hilgert 2009b]. In 64 Japanese families, five mutations were found in *CDH23* [Wagatsuma et al., 2007].
