Hereditary Causes Of Hearing Impairment Biology Essay


Hearing is among five major senses and it enables the humans to perceive threshold sound.. Deafness or hearing impairment means spoil of capability of an individual to acquire language and efficient verbal communication expertise. Deafness is is the most widespread perception depression (Van et al., 2005) and this sensori-neural disorder holds considerable prevalence among birth defect (Hilgert et al., 2009). Lot of reseasons have been established to affect the hearing ability including genetic and environmental factors. Almost 30% of the human population is suffered by this anarchy at any time. Out of 1000 infants, 1.9 are adversely affected by the hearing disorder (Morton and Nance, 2006). So far 49 genes have been identified and more than 90 loci with no corresponding genes in addition have been mapped causing loss to hearing (Van and Smith, 2009). The dominance and sources of congenital and intense prelingual deafness can be unlike at different times along with different populations (Tekin and Arici, 2007).

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The inheritance pattern of hearing impairment (HI) in most cases is autosomal recessive (80%) & dominant (17%), sex-linked (2-3%), and mitochondrial (<1%) inheritance also occur. In 30% of cases additional physical findings lead to the diagnosis of 1 of >400 syndromes in which HI can be a clinical component and in rest ofthe 70% of cases non-syndromic HI has been diagnosed (Morton, 1991).

Different parameters have been formulated to categorize the hearing impairment. Conductive hearing impairment is characterized when outer middle ear encounters any shortcoming while any fault to the inner ear lead to sensori-neural hearing impairment. Mixed HI does occur due to the presence of both these situations. Based on the age of commencement hearing impairment can be prelingual (before speech development) or postlingual (after speech development). Genetic causes count more than 70% to hearing impairment of prelingual cases while others include environmental factors and unknown genetic reseaons (Kenneson and Cannon, 2007).

Inheritance of HI is mostly monogenic. Non-syndromic HI is characterized when no other physical factor is involved there in otherwise it will be classified as syndromic (Van et al., 1997). So far more than 400 syndroms relating to the hearing loss have been characterized. Of these, Usher syndrome, Pendred syndrome and Jervell & Lange-Nielsen syndrome are considered most common (Toriello et al., 2004). The normal frequency for human hearing is ranged from 250-8000 Hz (Seelay et al., 1995) and is measured in decibels (dB). Threshold frequency indicates the intensity or level of sound at which a normal young individual can recognize a tone, also called 0dB. Normal hear usually occurs at threshold of 15dB for a normal young adult.

Mechanism of Normal Hearing

Outer, middle and inner ears are the major compartments, the auditory system comprised of. Sound impulses enter into this system through outer ear and are transmitted to tympanic membrane via external auditory canal. the tympanic membrane vibrates in turn and such vibrations are passed on to the inner ear through middle ear three auditory bones. Here these sound waves are altered into neural electrical impulses which are finally conveyed through a system of nerves to the auditory cortex of the brain for their translation (Hudspeth et al., 1989, Markin et al., 1995, Nobili et al., 1998).


Among factors responsible for the hearing loss, genetic factors are most prevalent and at the same time hereditary of such factors plays a significant role in the hearing disorders. Genetically hearing impairments may be syndromic (due to participation more than one organs/ or organ systems) or non-syndromic (due to the damage to the inner ear only; Gorlin et al., 1995; Van and Smith, 1998).

Non- Syndromic Hearing Impairment

Non-syndromic disorders are common among hereditary hearing losses (Morton, 1991). such forms of hearing disorder can be identified by knowing their mode of inheritance and associated malfunctioning of auditory system.. Monogenic prelingual hearing impairment is inherited as autosomal recessive, autosomal dominant, sex-linked and mitochondrial (Robertson and Morton, 1999). This hearing disorder is enormously heterogeneous (Van et al., 1997). Currently 51 nuclear genes and 135 loci are known for their influence on non-syndromic hearing impairment, of which 47 are concerned with autosomal dominant, 62 with autosomal recessive, 7 loci are X-linked, 1 is Y-linked and 2 loci are associated with mitochondrial inheritance (Van and Smith, 2006). Kunst et al. (1999) defined a prefix for each of the loci associated with non-syndromic hearing loss such that autosomal dominant, recessive and X-linked were prefixed as DFNA, DFNB and DFN , respectively. Genes modifying the expression of other genes influencing the hearing loss are prefixed as DFNM (Denoyelle et al., 1999).

Autosomal Recessive Non- Syndromic Hearing Impairment

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It contributes almost 80% of hearing impairment cases in infants and is controlled by at least 30 genes (Van and Smith, 2008). However, mutated genes, GJB2 and GJB6, localized for autosomal recessive non-syndromic hearing loss (ARNSHL) are responsible for almost 50% of the cases of autosomal recessive prelingual HI (Sukarova et al., 2009). Mutations only in one gene GJB2 are responsible for 30-50% of all extreme non-syndromic hearing losses in most of the populations (Denoyelle et al., 1999). The other 50% of cases are attributed to mutations in numerous other genes, many of which have been found to cause deafness in only one or two families (Hilgert et al., 2009). GJB2 is the gene which encodes connexin 26, a hexameric gap-junction protein widely expressed in supporting cells and connective tissues of the cochlea. The connexin hexamers on the surface of adjacent cells bind together to form intercellular channels thus allowing recycling of potassium ions from hair cells to the stria vascularis where they are actively pumped back into the cochlear endolymph (Forge et al., 2003). The maintenance of a high endocochlear potential by potassium recycling is of critical importance for sound perception. Although deafness caused by mutation of GJB2 was considered as profound in degree and congenital in onset it is now known to show considerable phenotypic variation (Murgia et al., 1999, Cryns et al., 2004). As more than 100 mutations involving GJB2 have been identified but a single variant designated 35delG, accounts for up to 70 percent of all pathologic mutations in many populations (Pandya et al., 2003).

Most cases of genetic deafness result from mutations involving a single gene, but a small and growing number are being identified in which hearing loss is determined by mutations in two independent genes. For example, DFNB1 can result from two mutations involving GJB2, two mutations in the closely linked GJB6 gene, or a combination of mutations involving both genes (the combination of mutations accounts for about 8 percent of DFNB1 cases) (Pandya et al., 2003). GJB6 is a gene with sequence similarity to GJB2 and is also expressed in the cochlea its product connexin 30 can form heteromeric gap-junction channels with connexin 26 subunits thus explaining the observed cases of digenic transmission.

Autosomal Dominant Non- Syndromic Hearing Impairment

Autosomal dominant forms constitute 18% of non-syndromic hearing loss (NSHL). The pedigree is usually vertical. Almost 50% of the siblings are affected. Hearing loss is mostly postlingual except for DFNA3, DFNA6, DFNA8, DFNA12, DFNA19 and DFNA14 (Bayazit and Yilmaz, 2006).

The person with an autosomal dominant non-syndromic hearing impairment has a postlingual hearing loss that begins in the second to third decades of life. The condition is extremely heterogeneous with multiple genes implicated in its pathogenesis. Audioprofiles may be distinct and therefore useful in predicting candidate genes for mutation screening (Amit et al., 2007). Heterogeneity is high in families with an autosomal dominant non-syndromic hearing impairment and there is not an identifiable single gene for this kind of deafness (Hildebrand et al., 2008).

Sex-Linked Non- Syndromic Hearing Impairment

The first nuclear gene implicated in non-syndromic hearing impairment was identified in 1995 and it was X-linked POU3F4 gene (Tranebjaerg, 1995). Some of the disease genes located on the X chromosome cause many human syndromes associated with hearing loss but few X-linked loci for non-syndromic hearing loss have been mapped. A Y-linked

locus has also been identified which shows one of the only disease loci on the Y chromosome (Petersen et al., 2008).

The X-linked inheritance involves particular genes located on the X chromosome. It more commonly affects male because they possess a single X chromosome and will present phenotypically with any mutation on the X chromosome. Female can carry the mutation on one of the X chromosomes without phenotypic expression. Her sons have a 50% chance of inheriting the mutation and express phenotypically. The daughters have a 50% chance of inheriting the mutation and become a carrier of the mutation (Francis et al., 2004). DFN3 is the locus for X-linked non syndromic hearing impairment which is mapped to Xq21.1. DFN3 is a mixed (conductive and sensorineural) hearing loss.

The causative gene for DFN3 is POU3F4 (Vore et al., 2005). Another locus for X-linked non syndromic hearing impairment is DFN2 which cause progressive sensorineural severe to profound hearing loss.

Mitochondrial Non- Syndromic Hearing Impairment

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Hearing loss can also be the sole symptom of mitochondrial disease suggesting that hearing is strongly dependent on mitochondrial function. Inherited deafness associated mtDNA mutations usually occur in the genes encoding components of the protein-synthesizing apparatus i.e rRNAs and tRNAs. Various mtDNA mutations causing progressive non-syndromic hearing loss have been identified. Mutations in 12S rRNA gene and tRNA gene account for most cases of maternally inherited nonsyndromic deafness (Guan, 2004).

Non-syndromic deafness-linked mutations are often homoplasmic or at high levels of heteroplasmy indicating a high threshold for pathogeneicity (Hutchin and Cortopassi, 2005). Other factors such as nuclear modifier genes, environmental factors, or mitochondrial haplotypes are involved in the Phenotypic expression of these mtDNA mutations (Guan, 2004). Hearing loss due to mtDNA mutations is usually of late childhood or early adulthood onset and progressively worsens with advancing age (Hutchin and Cortopassi, 2000).

Acquired mtDNA mutations are also found to be involved in the development of presbyacusis, the hearing loss that occurs with age in a significant proportion of individuals (Hutchin and Cortopassi, 2005). Most of the mutations in mitochondrial genes cause many different maternally inherited multisystem disorders but the mutations in genes mainly MT-RNR1 and MT-TS1 are responsible for nonsyndromic hearing loss (Fischel-Ghodsian, 1998). The MT-RNR1 gene encodes for the 12S ribosomal RNA. One mutation in this gene A1555G cause maternally inherited non-syndromic hearing loss (Kokotas et al., 2007).

2. Syndromic Hearing Impairment

Genetics of Syndromic Hearing Loss

More than 300 forms of syndromic hearing loss are present in which distinctive associated clinical features are a constant or at least an occasional feature have been observed (Toriello et al., 2004). In some of the cases several such genes that can cause the same phenotype or a closely related one have been identified. In some other cases observed variation in the severity or clinical findings can be attributed to different mutations of the same gene resulting in a genotype-phenotype correlation (Reardon et al., 1997). Syndromic hearing impairment accounts for up to 30% of prelingual deafness but its relative contribution to all deafness is smaller because of the impact of postlingual hearing loss (Amit et al., 2007). syndromic hearing loss can be inherited as:

Autosomal dominant inheritance (Waardenburg syndrome, Branchio-oto-renal syndrome, Stickler syndrome, Neurofibromatosis 2, Treacher Collins and Osteogenesis imperfecta).

Autosomal recessive inheritance (Pendred's syndrome, Usher syndrome, Jervell and Lange-Nielsen syndrome, Biotinidase deficiency and Refsum disease).

Sex-linked (Alport syndrome and Norrie disease).

Mitochondrial inheritance.

Modifier Genes

Modifier genes are the genes which qualitatively or quantitatively change or modify the phenotype produced by another gene. These genes may affect penetrance, dominance modification, progression, expressivity, pleiotropy, and age of onset (Nadeau, 2001). A modifier gene is generally a single allele, though homozygous alleles are expected to produce a quantitatively greater effect. Modifier genes alter the phenotypic effects of other genes but these may independently express a phenotype. Therefore in a complex pathway one gene may be considered to be modified by the other genes in the pathway. Such interactions potentially involve multiprotein structures, intracellular processes, and intercellular communication. There are multiple examples of modifiers in mice and humans (Nadeau, 2003). In humans fewer modifiers of hearing have been identified as the locus for a modifier gene DFNM1 for the deafness in DFNB26 has been identified on chromosome 1q24 (Riazuddin et al., 2000). Some modifier genes in hearing loss affect the mitochondria as a transcription factor and two enzymatic modifiers of mitochondrial RNA were shown to affect the well-characterized A1555G mtDNA mutation (Bykhovskaya et al., 2004a, 2004b). Another deafness locus DFNA11 with a varying severity has also been detected due to a single mutation in MYO7A, which shows the effect of modifier genes (Street et al., 2004).

Reported Genes For DFNB

Many different DFNB proteins have been implicated in deafness including proteins involved in the cytoskeleton such as the myosins, structural proteins such as the tectorin protein, ion transport proteins including several gap junction proteins and ion channels, and several genes with unknown function. Most of the deafness genes identified so far are large with many exons and no mutational hotspots. Only the GJB2 gene is small with only one coding exon(Petersen and Willems, 2006).

GJB2 (connexin 26) - DFNB1

The most important locus for non-syndromic autosomal-recessive deafness (DFNB1) was mapped to chromosome 13q11 by linkage analysis in families with pre-lingual, profound deafness (Guilford et al., 1994). Further studies revealed this locus as a major contributor to pre-lingual deafness. This locus contains GJB2 gene encoding the gap junction protein connexin 26 which had been mapped to 13q11-q12 (Mignon et al., 1996). The GJB2 gene was the first DFNB gene to be identified in 1997. Mutations in this gene were identified in three consanguineous Pakistani families with profound deafness genetically linked to 13q11 (Kelsell et al., 1997). The GJB2 gene has a single coding exon and the protein belongs to the large family of connexins having four transmembrane domains, which have been implicated in gap-junctional intercellular communication (Kumar and Gilula, 1996). Six connexin subunits bind together to form a hexamer (connexon) in the plasma membrane, and each connexon associates with another connexon in an adjacent cell to form an intercellular channel and multiple channels form cluster in a specialized membrane region to form a gap junction (Kumar and Gilula, 1996).

Connexons are important for recycling of potassium ions into the cochlear endolymph through the network of gap junctions that extends from the epithelial supporting cells to the fibrocytes of the spiral ligament and to the epithelial marginal cells of the stria vascularis (Holt and Corey, 1999, Steel, 1999). The ion homeostasis is important for normal hearing, and mutations in genes encoding connexins or ion channels lead to hereditary deafness (Holt and Corey, 1999, Rabionet et al., 2000). Mutations in the GJB2 gene are responsible for 50% of pre-lingual, non-syndromic, recessive deafness (Zelante et al., 1997, Denoyelle et al., 1997, Scott et al., 1998, Kelley et al., 1998, Rabionet et al., 2000, Kelsell , 2001, Kenneson et al., 2002).

GJB6 (connexin 30) - DFNB1

Another gene at DFNB1 locus is the GJB6 gene encodes connexin 30 and is located next to the connexin 26 gene. A GJB6 gene encompassing deletion of 342-kb was detected in 2002 (Del Castillo et al., 2002). Majority of the deaf individuals are heterozygous for one GJB2 mutation suggesting the existence of one or more unknown GJB2 mutations in the non-coding region of GJB2, possibly involving the same control region as the deletion.

Alternatively digenic inheritance is also possible, because both genes are expressed in the inner ear and also have 77% identity in amino acid sequence (Lautermann et al., 1998, Kelley et al., 1999). Another 232-kb deletion in the DFNB1 locus has been identified by Del Castillo et al., 2005.

Only one dominant GJB6 mutation associated with non-syndromic deafness has been identified (Del Castillo et al., 2005). GJB6 missense mutations also cause an inherited autosomal dominant skin disorder, hidrotic ectodermal dysplasia (Clouston syndrome), which is sometimes associated with hearing loss (Lamartine et al., 2000).

MYO7A (myosin VIIA) - DFNB2

The DFNB2 locus was mapped to 11q13.5 in a family with non-syndromic, profound deafness (Guilford et al., 1994). The MYO7A gene was the second DFNB gene to be associated with recessive, non-syndromic deafness (Weil et al., 1996, Tuxworth and Titus, 2000). MYO7A mutations were detected in 1997, in families with non-syndromic, congenital, profound hearing loss (Liu X-Z et al., 1997). Myosins are a family of actin-based molecular motors. Unconventional myosins have functions that are less well understood but thought to regulate intracellular membrane traffic. They are actin-based motor molecules which transduce chemical energy into the production of a force enabling them to move along actin filaments (Weil et al., 1996, Tuxworth and Titus, 2000). All myosins have a common structure with a conserved NH2-terminal motor domain followed by a variable number of light-chain binding motifs and a highly divergent tail. The MYO7A gene consists of 48 coding exons (Weil et al., 1996). MYO7A gene is expressed in sensory hair cells suggesting that deafness might result from a defective morphogenesis of the hair cell stereocilia, which is critical for the mechanotransduction process (Weil et al., 1996). More than 50 distinct MYO7A mutations have been reported in USH1B, four different mutations in DFNB2 and two in dominant deafness (DFNA11) (Tamagawa et al., 1996, Liu et al., 1997, Bolz et al., 2004). The mutations are present throughout the MYO7A gene (Janecke et al., 1999).

MYO15 (myosin XV) - DFNB3

DFNB3 locus was mapped to chromosome 17p (Friedman et al., 1995). The human MYO15 gene was identified and mapped to the DFNB3 critical region (Wang et al., 1998). Sequencing of the MYO15 gene showed three novel homozygous mutations segregating in three of the Pakistani families. MYO15 mutations are responsible for at least 5% of recessive, profound hearing loss (Liburd et al., 2001). Full-length human myosin XV is encoded by 66 exons (Liang et al., 1999) and expressed in a number of tissues in addition to the inner ear (Wang et al., 1998). Myosin XV is necessary for actin organization in hair cells (Probst et al., 1998, Anderson et al., 2000).

SLC26A4 (pendrin) - DFNB4

SLC26A4 mutations were detected in individuals with sensorineural hearing loss and temporal bone abnormalities (Usami et al., 1999, Scott et al., 2000, Campbell et al., 2001, Tsukamoto et al., 2003). SLC26A4 mutations were found in approximately 5% of the pre- lingual cases of deafness (Park et al., 2003). SLC26A4 encodes a transmembrane protein pendrin, which functions as a transporter of chloride and iodide and is expressed in the thyroid gland, the inner ear and the kidney (Scott et al., 1999). Studies revealed that mutations associated with Pendred syndrome have complete loss of chloride and iodide transport, while mutant alleles in patients with DFNB4 are able to transport both iodide and chloride, although at a much lower level than wild-type pendrin (Scott et al., 1999). SLC26A4 controls fluid homeostasis in the membranous labyrinth, which in turn affects development of the bony labyrinth (Campbell et al., 2001). In the majority of cases, one or two SLC26A4 mutations have been identified (Park et al., 2005, Pryor et al., 2005).

TMIE (transmembrane inner ear expressed gene)- DFNB6

Mutations in the human TMIE were detected in DFNB6. TMIE protein exhibited no significant similarity to any known protein and expressed in many human tissues (Naz et al., 2002). The exact function and location of the TIME protein is not completely known but it is estimated that this protein is required during maturation of hair cells (Mitchem et al., 2002).

TMC1 (transmembrane cochlear-expressed gene 1)- DFNB7

DFNB7 locus was mapped to chromosome 9q13-q21 (Jain et al., 1995). A novel gene termed TMC1 was identified within the critical interval and seven different TMC1 mutations were identified (Kurima et al., 2002). The mutations included nonsense, frameshift, missense, genomic deletion and splice-site mutations all in homozygous state (Kalay et al., 2005). A heterozygous missense mutation in TMC1 has also been reported in autosomal-dominant, post-lingual, rapidly progressing hearing loss (DFNA36) (Kurima et al., 2002). The TMC1 gene was shown to belong to a family of transmembrane channel-like (TMC) genes with eight paralogs (TMC1-TMC8) predicted to encode proteins with 6-10 transmembrane domains and a novel conserved 120-amino acid sequence termed the TMC domain (Kurima et al., 2003). TMC1 expression is detected in human fetal cochlea (Kurima et al., 2002).

TMPRSS3 (transmembrane serine protease) -DFNB8/DFNB10

TMPRSS3 gene (transmembrane protease, serine 3) is a novel gene (Hattori et al., 2000), within DFNB8/DFNB10 and mapped to chromosome 21q22.3 (Veske et al., 1996, Bonne-Tamir et al., 1996, Scott et al., 2000, Berry et al., 2000). Direct sequencing of the TMPRSS3 gene revealed a homozygous splice-site mutation resulting in a frameshift in DFNB8 (Scott et al., 2001). The DFNB10 reveals a deletion of 8 bp and insertion of 18 complete β-satellite repeat monomers in exon 11 of the TMPRSS3 gene. Homozygous TMPRSS3 mutations were detected (Ben-Yose et al., 2001). The TMPRSS3 gene has 13 exons encoding transmembrane low-density-lipoprotein receptor A (LDLRA), scavenger-receptor cysteine-rich (SRCR), and serine protease domains (Scott et al., 2001). EnaC (Epithelial sodium channel) was considered as a substrate for TMPRSS3 and it significantly activates ENaC whereas TMPRSS3 missense mutations causing DFNB8/DFNB10 deafness failed to activate ENaC (Guipponi et al., 2002).

OTOF (otoferlin) - DFNB9

DFNB9 locus with OTOF (otoferlin) gene was mapped to chromosome 2p23-p22 (Chaib et al., 1996). The human OTOF gene was shown to be composed of 48 coding exons predicting a 1997-amino acid protein otoferlin with alternatively spliced transcripts predicting several long isoforms and short isoforms (Yasunaga et al., 2000). Mutations reported for otoferlin include a splice-site mutation (Adato et al., 2000), a nonsense mutation (Houseman et al., 2001), two missense mutations (Leal et al., 1998, Mirghomizadeh et al., 2002) and a premature stop codon in exon 22 (Migliosi et al., 2002). OTOF mutations have also been described in non-syndromic, recessive auditory neuropathy. Strong expression was detected in cochlea, vestibule and brain (Yasunaga et al., 1999).

CDH23 (otocadherin) - DFNB12

The CDH23 gene is a very large gene consists of 70 exons encoding 3353 amino acids (Bork et al., 2001) and was mapped to chromosome 10q21-q22 (DFNB12) (Chaib et al., 1996). A total of 36 different CDH23 mutations were identified in families with recessive, non-syndromic deafness suggesting that as much as 5% of nonsyndromic deafness is caused by mutations in the CDH23 gene (Astuto et al., 2002). The CDH23 gene belongs to the cadherin superfamily of intercellular adhesion proteins that typically have large extracellular domains, a membrane-spanning region and cytoplasmic domains (Nollet et al., 2000). currently it has been observed that cadherin 23, harmonin (DFNB18) and myosin VIIA (DFNB2) work in a single functional network essential for the cohesion of the stereocilia of the hair bundle (Siemens et al., 2002, Boeda et al., 2002). Recently CDH23 is shown to be part of the tip links involved in cross-linking stereocilia (Di Palma et al., 2001, Siemens et al., 2004).

STRC (stereocilin) - DFNB16

The STRC (stereocilin) gene was mapped to chromosome 15q15-q21 (Campbell et al., 1997) contain 29 coding exons and was shown to be tandemly duplicated with a stop codon in exon 20. The deduced protein stereocilin shows no significant homology to any other known protein, stereocilin is expressed only in the sensory hair cells (Verpy et al., 2001).

USH1C (harmonin) - DFNB18

DFNB18 locus was mapped to chromosome 11p15.1-p14 (Jain et al., 1998), encompassing the region for Usher syndrome type 1C (USH1C) (Smith et al., 1992). The USH1C gene was shown to contain 28 exons and encodes a protein harmonin. A splice-site mutation in intron12 of the USH1C gene was detected (Verpy et al., 2000). Harmonin is only rarely implicated in non-syndromic deafness (Ouyang et al., 2002). Harmonin is expressed in the sensory areas of the inner ear, especially in the cytoplasm and stereocilia of hair cells (Verpy et al., 2000). Harmonin binds to otocadherin ( DFNB12) and to interact with myosin VIIA ( DFNB2) and form a coherent hair cell bundle (Siemens et al.,2002, Boeda et al., 2002). Mutations of the USH1C gene cause a progressive loss of hair cells and a secondary degeneration of spiral ganglion cells. The hair cell degeneration was preceded by disorganization of stereocilia (Johnson et al., 2003).

TECTA (α-tectorin) - DFNB21

DFNB21 was identified in a region on chromosome 11q23-q25 encompassing the TECTA gene responsible for DFNA8/DFNA12 deafness (Verhoeven et al., 1997, Kirschhofer et al., 1998, Verhoeven et al., 1998). Mutations reported in TECTA gene include a splice-site mutation in intron 9 of TECTA gene (Mustapha et al., 1999), frameshift mutations (Naz et al., 2003) and dominant TECTA missense mutations (Alloisio et al., 1997, Verhoeven et al., 1998, Balciuniene et al., 1999). TECTA encodes α-tectorin, one of the major non-collagenous extracellular matrix components of the tectorial membrane that bridges the stereocilia bundles of the sensory hair cells (Legan et al., 2000).

OTOA (otoancorin) - DFNB22

The human OTOA (otoancorin) gene consists of 28 exons and maps to chromosome 16p12.2 (Zwaenepoel et al., 2002). It is expressed in inner ear and acts as an adhesion molecule (Chang and Pastan, 1996, Zwaenepoel et al., 2002), that mediate attachment of the tectorial membrane in the cochlea and the otoconial membranes and cupulae in the vestibule. Only a splice-site mutation at the exon 12/intron 12 junction was found to co-segregate with the hearing impairment (Zwaenepoel et al., 2002). This indicates that OTOA mutations are not frequent causes of deafness.

PCDH15 (protocadherin 15) - DFNB23

The PCDH15 gene was thought to be a good candidate for non-syndromic hereditary deafness with a missense mutation (Ahmed et al., 2003). PCDH15 gene encodes protocadherin 15 and initially it was considered to be responsible for Usher syndrome type 1F (Ahmed et al., 2001, Alagramam et al., 2001). This gene was detected to be present along the length of stereocilia, in the cuticular plate, and diffusely distributed in the cytoplasm of inner and outer hair cells (Ahmed et al., 2003) and mutations in this gene cause disorganization of stereocilia bundles and degeneration of inner ear neuroepithelia (Alagramam et al., 2001).

CLDN14 (claudin 14) - DFNB29

The DFNB29 locus was mapped to chromosome 21q22.1. This critical interval contained the CLDN14 gene which was thought to be a good candidate gene. In this gene a single nucleotide deletion in transmembrane domain 2 was identified (Wilcox et al., 2001). Claudins comprise a multigene family of integral membrane proteins identified as major cell adhesion molecules working at intercellular tight junctions (Tsukita and Furuse, 2000). claudin 14 expression was observed in the inner and outer hair cell region of the organ of Corti and in the sensory epithelium of the vestibular organs (Wilcox et al., 2001). Absence of claudin 14 from tight junctions in the organ of Corti leads to altered ionic permeability of the paracellular barrier of the reticular lamina and prolonged exposure of the basolateral membranes of outer hair cells to high potassium concentrations may be the cause of cell death of hair cells (Ben-Yosef et al., 2003).

MYO3A (myosin IIIA) - DFNB30

DFNB30 locus was mapped to chromosome 10p (Walsh et al., 2002). The MYO3A mapped within the DFNB30 region and seemed to be an excellent candidate (Dose and Burnside, 2000), as four other myosins had been associated with hearing loss (Walsh et al., 2002). Three different loss-of-function MYO3A mutations were identified to segregate with hearing loss. Myosin IIIA is an actin-dependent motor protein belonging to the class III unconventional myosins. MYO3A has a function in the mechanotransduction process but the exact function in the mammalian ear remains to be investigated (Dose and Burnside, 2000).

WHRN (whirlin) - DFNB31

DFNB31 was identified to be responsible for pre-lingual, profound hearing impairment and mapped to chromosome 9q32-q34 (Mustapha et al., 2002). WHRN (whirlin) a novel gene was identified in this region (Mburu et al., 2003). A deletion of 592 bp and a nonsense mutation was detected in WHRN (Mustapha et al., 2002). This human gene was shown to comprise 12 exons (Mburu et al., 2003). whirlin acts by controlling actin polymerization and membrane growth of stereocilia (Mburu et al., 2003, Kikkawa et al., 2005). The elongation of stereocilia was found to be defective in recessive deafness mutant whirler (wi) homozygotes with eventual degeneration of both inner and outer hair cells (Holme et al., 2002).

ESPN (espin) - DFNB36

The DFNB36 locus cotaining ESPN (espin) was mapped on chromosome 1p36.3. Two homozygous ESPN frameshift mutations has been detected in the two Pakistani families. The human ESPN gene consists of 13 exons and was observed to encode an 854 amino acid protein (Naz et al., 2004). The espins are actin-bundling proteins. This gene espin was predicted to be localized mostly to the stereocilia of inner ear and defective expression of espin cause complete loss of sensory hair cells (Zheng et al., 2000).

MYO6 (myosin VI) - DFNB37

DFNB37 locus was found to be localized on chromosome 6q13 (Ahmed et al., 2003). MYO6 gene encoding myosin VI was observed on this locus (Melchionda et al., 2001). Mutation screening of the MYO6 gene identified homozygous mutations in the three Pakistani families (Ahmed et al., 2003).

The MYO6 gene is an unconventional myosin highly expressed at the base of the stereocilia of the inner and outer hair cells (Avraham et al., 1997). Defective expression of MYO6 results in the degeneration of hair cells and giant stereocilia (Avraham et al., 1995).

COL11A2 (collagen 11a2) - DFNB53

COL11A2 gene containing DFNB53 locus was identified on chromosome 6p21.3. Many mutations were identified in COL11A2 gene as missense mutation in exon 21 (Chen et al., 2005), recessive mutations in otospondylomegaepiphyseal dysplasia (OSMED) (Melkoniemi et al., 2001) and dominant mutations in non-ocular Stickler syndrome (Vikkula et al., 1995), all syndromic types of hearing loss. A phenotype-genotype comparison indicates that mutation type and location are critical determinants in describing the phenotype of COL11A2-associated diseases (Chen et al., 2005).

GJB3 (connexin 31)

The GJB3 gene which encodes the gap junction protein connexin 31 was mapped to chromosome 1p35-p33 after cloning and thought to be a good candidate for hereditary hearing impairment (Xia et al., 1998). Currently none of the known DFNB loci maps to the 1p35-p33 chromosomal region (Liu et al., 2000). Some of the GJB3 mutations reported with unknown significance include a heterozygous GJB3 mutation (Uyguner et al., 2003), a heterozygous R32W mutation in two patients with late onset hearing loss (Mhatre et al., 2003), autosomal-dominant high-frequency hearing loss (DFNA2) (Xia et al., 1998) and a 3-bp GJB3 deletion (Lopez-Bigas et al., 2001). GJB3 mutations are also responsible for autosomal-dominant erythrokeratodermia variabilis (EKV) (Richard et al., 1998), whereas recessive EKV was also identified due to a homozygous GJB3 missense mutation (Gottfried et al., 2002). The identified GJB3 protein connexin 31 has four hydrophobic transmembrane domain-like motifs and sharing 76% homology with GJB2 (Kumar and Gilula, 1996, Xia et al., 1998). GJB3 expression was detected in cortex, spinal cord and inner ear (Xia et al., 1998).

GJA1 (connexin 43)

GJA1 gene encoding the gap junction protein connexin 43 was mapped on 6q21-q23.2 (Fishman et al., 1990, Corcos et al., 1993). Mutations in the GJA1 gene cause oculodentodigital dysplasia syndrome (Paznekas et al., 2003) and syndactyly type 3 (Britz-Cunningham et al., 1995). Although GJA1 was considered as a candidate for non-syndromic deafness with a missense mutation (Liu et al., 2001) but the role of GJA1 in deafness is not clearly determined.

SLC26A5 (prestin)

The human SLC26A5 gene localized on chromosome 7q22.1 has 21 exons encoding a protein prestin with a highly hydrophobic core of 12 transmembrane domains with the N- and C-terminals located cytoplasmically (Liu et al., 2003).

Prestin belongs to the solute carrier (SLC) gene family 26, which encodes anion-transporter-related proteins. Nine human SLC26A genes have been identified, and mutations in the SLC26A4 genes are responsible for Pendred syndrome/DFNB4 (Everett and Green, 1999, Lohi et al., 2002). This suggests prestin a good candidate gene for genetic deafness. It is specifically and highly expressed in outer hair cells lining the lateral wall in a close-packed array (Dallos and Fakler, 2002, Liu et al., 2003). It is a motor protein of cochlear outer hair cells, it contribute to amplification of vibrations in the cochlea that are transduced by inner hair cells (Zheng et al., 2000).

ATP2B2 modifier gene

Hearing loss due to mutations in CDH23 or MYO6 can be modified by heterozygosity for a hypofunctional variant in the ATP2B2 gene which encodes the plasma-membrane calcium pump PMCA2 (Schultz et al., 2005) which shows that these genes are interacted with one another.

Environmental causes of Hearing Impairment

Hearing loss is an etiologically heterogeneous trait with many known genetic and environmental causes. Among the environmental causes of hearing loss prematurity, prenatal and postnatal infections, head trauma, subarachnoid hemorrhage, and pharmacologic ototoxicity are most important (Morton and Nance, 2006).

In children hearing loss frequently results from prenatal infections from "TORCH" organisms (toxoplasmosis, rubella, cytomegalic virus, and herpes), or postnatal infections of which the most important is bacterial meningitis caused by many microorganisms. The most common environmental (non-genetic) cause of congenital hearing impairment is congenital cytomegaloviral (CMV) infection. The overall birth prevalence of congenital cytomegaloviral (CMV) infection is 0.64%, and only about 10% of this number have symptomatic CMV. Of asymptomatic cases 0-4.4% develops unilateral or bilateral hearing impairment before the age of 6 years. The diagnosis of congenital CMV is often difficult to make, especially in children over 3 weeks of age. (Kenneson and Cannon, 2007).

In adults the hearing loss may be caused by environmental factors but environmental-genetic interactions is most frequent. Age-related and noise-induced hearing losses are the commonly known examples of complex 'environmental-genetic' hearing loss however until today only a few genes have been identified which are associated with these complex traits (Huyghe et al., 2008, Konings et al., 2009).

In the present study two families from different areas of Azad Jammu and Kashmir with autosomal recessive non-syndromic hearing loss have been attended, genotyped and sequenced.