**4.1.2 Autosomal dominant non- syndromic hearing loss**

Late onset, mild and progressive forms of HL are the usual phenotypes associated with autosomal dominant form of deafness. About 25 genes and more than 60 loci have been reported for autosomal dominant non- syndromic hearing loss (ADNSHL). There is no frequent gene mutated in ADNSHL but mutations in some genes including *WFS1*, *KCNQ4*, *COCH* and *GJB2* have been suggested to be common (Kelsell et al., 1997; Nie 2008; Higert et al., 2009).

### **4.1.2.1** *WFS1* **gene and its protein**

The *WFS1* (Wolfram) gene at DFNA6 locus, located on 4p16, consists of 8 exons and has a length of about 33.4 kb and a 3.6 kb transcript. It codes for a polypeptide of 890 amino acids [Hofmann et al., 2003]. The Wolframin protein is a resident component of the endoplasmic reticulum (ER) and may be involved in membrane trafficking, processing and/or regulation of ER calcium homeostasis [Fonseca et al., 2010]. In the inner ear, however, this protein may be helpful to maintain the appropriate levels of calcium ions and/or other charged particles required for hearing process [Cryns et al., 2003].

Dominant mutations in *WFS1* can cause a characteristic type of HL which affects the low frequencies and less loss in hearing in the high frequencies [Bespalova et al., 2001; Fukuoka et al., 2007]. It has been shown that dominant mutations are usually located in the Cterminal domain. The recessive Wolfram syndrome is caused by numerous mutations distributed along the entire gene. Two mutations c.424\_425ins16 and c.1362\_1377del16 have a high frequency in some specific populations including Spanish patients and Italians, respectively [Gómez-Zaera et al., 2001; Colosimo et al., 2003]. It is hypothesized that, inactivating mutations may lead to Wolfram syndrome and missense mutations occurring in the C-terminal domain can cause the characteristic low-frequency ADNSHL [Cryns et al., 2003].

### **4.1.2.2** *KCNQ4* **gene and its protein**

The *KCNQ4* gene at DFNA2 locus, located on 1p34, consists of 14 exons and codes for a polypeptide of 695 amino acids, a voltage-gated potassium channel. It is a member of the KCNQ voltage-gated K+ channel family [Coucke et al., 1999]. It has an important role in K+

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.,

Non syndromic HL in a Pakistani family linked to a new region on chromosome 6p21.1 p22.3 defining a new locus, DFNB67 in 2006; *TMHS* or *LHFPL5* gene was mapped in this region [Shabbir et al., 2006]. *LHFPL5* has 4 exons and encodes a 2162 nucleotide mRNA and translates into a protein of 219 amino acids. The proposed structure of the protein is a four pass transmembrane domain. Mutations of this gene have been reported in patients from Pakistan and Turkey (C161F, Y127C, P83fsX84). *TMHS* is important for the

Late onset, mild and progressive forms of HL are the usual phenotypes associated with autosomal dominant form of deafness. About 25 genes and more than 60 loci have been reported for autosomal dominant non- syndromic hearing loss (ADNSHL). There is no frequent gene mutated in ADNSHL but mutations in some genes including *WFS1*, *KCNQ4*, *COCH* and *GJB2* have been suggested to be common (Kelsell et al., 1997; Nie 2008; Higert et

The *WFS1* (Wolfram) gene at DFNA6 locus, located on 4p16, consists of 8 exons and has a length of about 33.4 kb and a 3.6 kb transcript. It codes for a polypeptide of 890 amino acids [Hofmann et al., 2003]. The Wolframin protein is a resident component of the endoplasmic reticulum (ER) and may be involved in membrane trafficking, processing and/or regulation of ER calcium homeostasis [Fonseca et al., 2010]. In the inner ear, however, this protein may be helpful to maintain the appropriate levels of calcium ions and/or other charged particles

Dominant mutations in *WFS1* can cause a characteristic type of HL which affects the low frequencies and less loss in hearing in the high frequencies [Bespalova et al., 2001; Fukuoka et al., 2007]. It has been shown that dominant mutations are usually located in the Cterminal domain. The recessive Wolfram syndrome is caused by numerous mutations distributed along the entire gene. Two mutations c.424\_425ins16 and c.1362\_1377del16 have a high frequency in some specific populations including Spanish patients and Italians, respectively [Gómez-Zaera et al., 2001; Colosimo et al., 2003]. It is hypothesized that, inactivating mutations may lead to Wolfram syndrome and missense mutations occurring in the C-terminal domain can cause the characteristic low-frequency ADNSHL [Cryns et al.,

The *KCNQ4* gene at DFNA2 locus, located on 1p34, consists of 14 exons and codes for a polypeptide of 695 amino acids, a voltage-gated potassium channel. It is a member of the KCNQ voltage-gated K+ channel family [Coucke et al., 1999]. It has an important role in K+

2007].

transmission of sound.

**4.1.2.1** *WFS1* **gene and its protein** 

**4.1.2.2** *KCNQ4* **gene and its protein** 

required for hearing process [Cryns et al., 2003].

al., 2009).

2003].

**4.1.1.8** *TMHS* **or LHFPL5 genes in DFNB67 locus** 

**4.1.2 Autosomal dominant non- syndromic hearing loss** 

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; Akita et al., 2001].
