**5. Age-related HL**

224 Hearing Loss

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].

Gene Mutation Phenotype Reference

induced/worsened

induced/worsened

induced/worsened

myoclonus

and ataxia

deafness

deafness

Table 4. Identified mitochondrial DNA mutations in HL.

deafness/MELAS

parkinsonism, and neuropathy

including ataxia, dysarthria and

*MTTS1* 7444G>A NSHL/Aminoglycoside induced Pandya et al., 1999; (tRNASer(UCN)) 7445A->G NSHL/Palmoplantar keratoderma Fischel-Ghodsian, 2003

827A>G NSHL/Aminoglycoside induced Li et al., 2005

7510T->C NSHL/no additional symptoms Hutchin et al.2000 7511T->C NSHL/no additional symptoms Friedman et al., 1999

8332A>G dystonia, stroke-like episodes and HL Gal et al., 2010

NSHL/Aminoglycoside Estivill et al., 1998

NSHL/Aminoglycoside Zhao et al., 2004

NSHL/Aminoglycoside Bacino et al., 1995

NSHL/Aminoglycoside induced/ Zhao et al., 2004

NSHL/Neurological dysfunction, Jaksch et al., 1998

HL/Progressive myoclonic epilepsy Jaksch et al., 1998

maternally inherited diabetes and Goto et al., 1990

maternally inherited diabetes and Rigoli et al., 2001

maternally inherited diabetes and Kameoka et al., 1998

**4.1.4 Mitochondrial HL** 

*MTRNR1* (12S 1555A->G

1494C->T

(mutations)

1095T>C

7472insC

7512T>C

*MTTL1* 3243A>G

*tRNA* 8296A>G *Lys* 

*tRNA* 14709T>C *Glu* 

(tRNALeu(UUR))

961

rRNA) 

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 new approaches to identify at risk individuals.


Table 5. SNPs associated with ARHL.

Genetics of Hearing Loss 227

Fig. 3. Hypothetic structure and domains of Pendrin protein. The most common mutations (L236P, IVS8+1G>A, T416P, and H723R) accounting for approximately 60% of the total PS genetic load are shown. TM1-TM12 denotes transmembrane domains, EC1-6 denotes extracellular domains, IC denotes cytoplasmic domain, NT denotes amino (NH2) terminus

**Alport syndrome:** Alport syndrome, a hereditary disorder of basement membranes, is characterized by renal abnormalities including glomerulonephritis, hematuria ("red diaper") and renal failure, and ocular problems as well as progressive sensorineural HL [Wester et al., 1995]. Mutations in various genes encoding type 4 collagen (COL4A3, COL4A4 and COL4A5) have been reported to cause Alport syndrome [Lemmink et al., 1994; Hudson et al., 2003]; nearly 85% of the cases are due to COL4A5 mutations [Hudson et al., 2003]. These collagens are components of the basilar membranes, the spiral ligament and stria vascularis. X-linked pattern of inheritance is observed in the majority (80 %); the remaining shows autosomal recessive [Lemmink et al., 1994] and autosomal dominant [van der Loop et al., 2000], inheritance patterns. It is estimated that 10% to 15% of X-linked patients represent de novo mutations in *COL4A5* [Gubler et al., 2007]. Since uremia leads to death in males prior to 30 years of age, it is essential to diagnose it early in men. Symptoms are usually more severe than women. The progressive sensorineural HL usually begins in the adolescent years [Wester et al., 1995]. The mechanism of HL has not been explained exactly yet, although the basement membrane damages are suggested to affect adhesion of the cells of the organ of Corti and basilar membrane leading to HL

**Waardenburg syndrome**: Waardenburg disease, named after Petrus Johannes Waardenburg (1886-1979), accounts for 1-3% of congenital HL [Read & Newton, 1997]. In addition, the disease shows other clinical features. Four types of syndrome can be distinguished on the basis of accompanying abnormalities [Read & Newton, 1997]: In type 1, patients show dystopia canthorum, iris heterochromy, brilliant blue eyes, broad nasal root, premature

and CT denotes carboxyl (COOH) terminus.

[Merchant et al., 2004].
