Contribution of connexin26 (GJB2) mutations and founder effect to non-syndromic hearing loss in India.

Congenital hearing loss has been documented to occur in 1 of 1000 live births, with over half of these cases predicted to be hereditary in nature. 2 Most hereditary hearing loss is inherited in a recessive manner, accounting for approximately 85% of non-syndromic hearing loss (NSHL). Deafness is an extremely genetically heterogeneous disorder, shown by the fact that 33 loci for recessive NSHL and 39 loci for dominant NSHL have been mapped to date (updated regularly on the Hereditary Hearing Loss Homepage: http://dnalabwww.uia.ac.be/dnalab/hhh/index.html). In populations with increased levels of consanguinity, such as India, congenital hearing loss is even higher. According to the 47th Round of the National Sample Survey Organisation (NSSO) taken in 1991 (http://www.healthlibrary.com/), 3 242 000 subjects over the age of 5 have a hearing disability, which is defined as a hearing impairment of 60 decibels and above in the better ear to total loss of hearing in both ears. Prelingual recessively inherited deafness has long been recognised in India. A significant number of the deafness loci have been discovered or found in the Indian population, facilitated by the large extended families and high rates of consanguinity. Seven deafness loci are currently known to be associated with deafness in India. These include DFNB3, DFNB5, DFNB6, DFNB7/B11, DFNB15, DFNB17, and DFNB18. In four of these seven cases, the associated gene has been cloned: transmembrane cochlear expressed gene 1 (TMC1) for DFNB7/B11, myosin XVA (MYO15A) for DFNB3, 12 transmembrane inner ear expressed gene (TMIE) for DFNB6, and harmonin for DFNB18. In many parts of the world, deafness associated with the DFNB1 locus on chromosome 13q11 is the most prevalent. Two genes localised to this chromosomal region have been implicated in deafness, including connexin26 (Cx26, gene symbol GJB2) and connexin30 (Cx30, GJB6). 17 In populations in which the genetic epidemiology of deafness has been evaluated, mutations in GJB2 are the single most frequent cause of inherited deafness. In certain northern European and Mediterranean populations, it accounts for 50% of childhood deafness. Connexins are gap junction proteins that oligomerise as hexamers to form transmembrane channels called connexons. Connexons from the cell membranes interdigitate to form direct intercellular communications pathways, the gap junction channels. Connexins have a highly conserved form of transmembrane domains separating two extracellular loops from a middle cytoplasmic loop and the Nand C-terminal cytoplasmic ends. In the inner ear, connexin26 is expressed in the supporting cells, stria vascularis, basement membrane, limbus, and spiral prominence of the cochlea. The sensory hair cells of cochlea allow potassium ions to pass through during the mechanosensory transduction process of normal hearing. These potassium ions are recycled across the supporting cells and fibrocytes at the base of hair cells through the gap junctions of the stria vascularis and back to the K rich endolymph. It is believed that mutations in the GJB2 gene would lead to complete or partial loss of function of the Cx26 protein, interfering with recycling of potassium ions and thus hampering the normal process of hearing. Removal of Cx26 in the epithelial network of the inner ear of mice does lead to deafness in these mice, indicating that Cx26 gap junctions are essential for cochlear function and cell survival. Many studies from various parts of the world have documented the incidence of GJB2 mutations in the deaf population. These include France, the United States, Israel, and, most recently, Lebanon, Greece, Austria, China, Brazil, and the Iranian and Palestinian populations. Updates covering all the connexin26 mutations are provided by the Connexin-Deafness Homepage (http:// www.crg.es/deafness/). Several of these studies included subjects from the Indian subcontinent. 19 32–34 However, none of these reports provided a systematic study of the prevalence of connexin26 mutations in the Indian population. In our study, we ascertained 215 profoundly deaf subjects and characterised the GJB2 mutations in this population.