Academic journal article Iranian Journal of Public Health

Genetic Linkage Analysis of DFNB3, DFNB9 and DFNB21 Loci in GJB2 Negative Families with Autosomal Recessive Non-Syndromic Hearing Loss

Academic journal article Iranian Journal of Public Health

Genetic Linkage Analysis of DFNB3, DFNB9 and DFNB21 Loci in GJB2 Negative Families with Autosomal Recessive Non-Syndromic Hearing Loss

Article excerpt

Introduction

Hearing loss is regarded as a common neurosensory disorder, and affects approximately 1-2 in 1000 live births (1). Hearing loss is a multifactorial defect caused by genetic, environmental factors or a combination of both (2). The role of genetic factors in the pathogenesis of hearing loss far outweighs the environmental parameters, and about 60% of the hearing loss is caused by genetic changes (3). The inheritance patterns of genetic hearing loss are autosomal recessive (77%), autosomal dominant (22%), X-linked (1%), and mitochondrial (<1%) (4). Based upon the presence or absence of distinctive clinical features, hearing loss can be classified into syndromic (20-30%) and non-syndromic (70-80%) forms (5). Autosomal recessive non-syndromic hearing loss (ARNSHL) is the most frequent hereditary form of hearing loss (HL), and displays a very allelic and locus het- erogeneity (6). To date, more than seventy loci have been mapped for ARNSHL by linkage analysis, and they are designated as DFNB followed by an identification number (7). Totally 40 genes have been identified in these loci (8).

In attempt to find candidate locus for ARNSHL, DFNB1 (MIM 220290) was initially identified by Guilford et al. which accounts for large percentage of ARNSHL (9, 10). In the DFNB1 locus, mutations in GJB2 gene, encoding the gap junction beta-2 protein connexin 26 are estimated to be responsible for 10-50% of ARNSHL in many populations (11). Therefore, the GJB2 gene mutations only explain a fraction of ARNSHL. Other common loci are associated with ARNSHL including DFNB3 (MYO15A gene, MIM 602666), DFNB9 (OTOF gene, MIM 603681) and DFNB21 (TECTA gene, MIM 603629) (8, 12). The role of DFNB3 locus in ARNSHL pathogenesis was initially identified in a population of villagers of Bengkala, Bali (13). The MYO15A gene within the DFNB3 locus encodes myosin XVA, an unconventional myosin, is a motor protein in hair cells of cochlea that deliver Whirlin protein to the tips of stereocilia, and play fundamental role in formation of stereocilia structure (9). Another gene, OTOF (DFNB9), encodes otoferlin, a large trans membrane protein, play an important role in exocytosis of synaptic vesicles at the synapse between inner hair cell and auditory nerve fibers (14). It has been previously reported that OTOF mutations lead to a unique form of ARNSHL called auditory neuropathy (15). The TECTA (DFNB21), a highly polymorphic gene, encodes alpha-tectorin, a glycoprotein that interacts with beta-tectorin to form the noncollagenous matrix of the tectorial membrane (16). The TECTA gene mutation may be disrupt the structure of this matrix that leads to insufficient transmission and amplification of sound in the inner ear (16).

Due to large number of consanguineous marriage in Middle East compared to European and American population, ARNSHL is 2-3 times more common in the Middle East (12). Iran, with a heterogeneous population due to various ethnicities and with high consanguineous marriage rate (38.6%), represents a worthy opportunity for genetic linkage analysis of ARNSHL (17).

Therefore, we aimed to address the question of "whether DFNB3, DFNB9 and DFNB21 loci can be contributed to ARNSHL or not," by genetic linkage analysis these loci in GJB2 negative families.

Materials and method

Families

In this descriptive study, 32 families with at least two affected children were identified from Hormozgan province of Iran, during 2013-2014. HL screening for members of the families was performed by pure tone audiometric test and clinical examination. HL informational questionnaires were obtained from all families and the pedigrees were drawn based on the filled-out questionnaires and interview with the members of the families by genetic counselors. Families with the following criteria were excluded from the study: syndromic hearing loss, exposure to known environmental risk factors such as trauma ototoxic drugs, rubella during pregnancy and excessive noise. …

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