**4.1.3 X and Y linked HL**

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 (http://hereditaryhearingloss.org/).

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].

Genetics of Hearing Loss 225

Biological changes accumulate in people during life as individuals age. About one hundred thousand individuals die each day of age-related causes around the world [de Grey, 2007]. Age-related HL (ARHL) or presbycusis is the most frequent sensory defect in the elderly people. It occurs due to accumulation of environmental and genetic changes i.e. gradual deleterious changes in the ear gives rise hearing impairment in older people. Approximately 25 % of 60 year olds and more than 50 % of 80 year ages suffer from ARHL [Dror & Avraham, 2009; Huang & Tang, 2010]. Many heterogeneous factors including family history, exposure to loud noises, ototoxic medication, exposure to chemicals, free radical (reactive oxygen species) chronic medical conditions, malnutrition, mtDNA mutations, alcohol abuse and smoking etc. may cause this type of HL [Van Eyken et al., 2007b; Huang & Tang, 2010]. Some common deletions and acquired mtDNA point mutations due to reactive oxygen spicies (ROS) have also been suggested to cause prebyscusis. Although genetic studies on ARHL are increasing in the recent years, there is a little information about the role of genes to its etiology. Two basic approaches have been used to identify susceptibility genes for ARHL: the linkage study and the association study [Van Eyken et al., 2007b]. Several single nucleotide polymorphisms (SNPs) have been reported to correlate with presbycusis; variants in *GRHL2*, *GRM7*, *KCNQ4* and N-acetyltransferase 2 are involved (Table 5) [Van Eyken et al., 2006, 2007a; Van Laer et al., 2008; Friedman et al., 2009]. Mutations in cadherin 23 coded by *CDH23* gene may also cause ARHL [Johnson et al., 2010]. More recently, a genome-wide association scan was conducted on ARHL in the genetically isolated Finnish Saami population. This study confirmed, and also provided further evidence for the role of the previous reported gene, *GRM7* in ARHL. *IQGAP2* gene was also proposed to be involved in presbycusis [van Laer et al., 2010]. Mechanism of ARHL is not well understood. However, new promising technology and strategies may help to discover the exact role of genetic mutations in presbycusis. Finding of the genetic variants causing ARHL will ultimately lead to discovery of new pharmaceutical interventions and the development of

**5. Age-related HL** 

new approaches to identify at risk individuals.

SNP12 (rs2149034) SNP18 (rs12143503)

NAT2\*6A (rs1799930)

42731C>T (rs2127034) 53110C>T (rs1981361)

75922504C>T (rs1697845)

36738A>G (rs10955255) *GRHL2* 

75920972A>G (rs457717) *IQGAP2* 

Table 5. SNPs associated with ARHL.

SNP (RS number) Gene Protein or Function

acetyltransfer

N-

ase 2

SNP9 (rs727146) *KCNQ4* Potassium channel (voltage-gated)

7155702T>A (rs11928865) *GRM7* glutamate receptor, metabotropic,7

metabolism of cytotoxic,

transcription factor cellular

IQ motif-containing GTPaseactivating-like protein

promoter 2-like 3

carcinogenic compounds and ROS

Van Eyken et al., 2006

Unal et al., 2005

Van Laer et al., 2008

Friedman et al., 2009

Van Laer et al., 2010

### **4.1.4 Mitochondrial HL**

In healthy individuals, only one type of mitochondrial DNA genotype (homoplasmy) exists, but in many mitochondrial diseases, mitochondrial genome has mixed genotype (heteroplasmy). Heteroplasmy differs from one tissue to another and can even differ within the cells of a tissue. A few genes contribute to mitochondrial HL [Fischel-Ghodsian, 2003]. Due to the important function of mitochondria in producing chemical energy through oxidative phosphorylation, mitochondrial DNA mutations can cause systemic neuromascular disorders such as HL. mtDNA mutations may be inherited or acquired (Table 4); the inherited mitochondrial mutations can cause many clinical features including myopathy, neuropathy, diabetes mellitus and sensorineural HL [Finsterer & Fellinger, 2005; Guan 2011]. Acquired mitochondrial mutations may be associated with aging and agerelated HL or presbycusis [Fischel-Ghodsian, 1999, 2003]. Multiorganic mitochondrial syndromes are often lethal in homoplasmic state. Mitochondrial homoplasmy exists in LHON (Leber Hereditary Optic Neuropathy) and maternal inherited HL [Fischel-Ghodsian, 2003]. Myoclonic epilepsy and ragged red fibers (MERRF), Kearns-Sayre syndrome (KSS) and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes are associated with progressive HL [Zeviani et al., 1998; Goto et al., 1990].


Table 4. Identified mitochondrial DNA mutations in HL.
