Halláskárosodásban részt vevő gének polimorfizmusai és mutációi roma és magyar populációkban

Abstract

Hearing loss is the most common sensory disorder, influences the normal communicationand affects more than 350 million people worldwide. Hearing loss has 3 main types. Conductivehearing loss occurs in the ear canal, the middle ear, the ear drum, or the bones in the middle earor in the membranous labyrinth. Sensorineural hearing loss develops in the inner ear, andaffected the auditory nerve, the auditory pathways, or the auditory cortex. The third type is themixed hearing loss. This is the combination of the conductive and sensorineural hearing loss.In most cases hearing loss is a multifactorial disorder, caused by genetic and environmentalfactors or a combination of these. However, one gene mutation also can cause the disease.Approximately, 200 genes are responsible for hearing, of which 30 are known.One of the best known genes, whose mutation causes hearing loss, is the GJB2 gene. GJB2has one coding exon, therefore it belongs to the group of small genes. Nowadays, more than 6autosomal dominants, and 70 autosomal recessive inherited genetic mutations have beenreported in the GJB2 gene. The W24X is a nonsense mutation causing recessive deafnessphenotype, and detected only in Indian populations.NAT2 gene plays an important role in the metabolism of reactive oxygen species (ROS) andthere is a correlation between NAT2 rs1799930 and the age-related hearing impairment. NAT2gene is highly polymorphic and there are 3 types of NAT2 enzyme metabolism: fast,intermediate, and slow acetylator phenotypes. These phenotypes show Mendelien inheritanceand all of them cause hearing loss.GRM7 has a central role in glutamate synaptic transmission and homeostasis in the cochleaat the synapses between the dendrites and hair cells of afferent auditory nerve fibers. Glutamatetoxicity plays a role in a formation of noise induced and age-related hearing loss in many ways.The presence of glutamate in large quantity causes neurotoxicity in auditory neuron, becauseof its stimulating property. A false allele of GRM7 changes the synaptic autoregulation ofglutamate in the synaptic gap of hearing neurons and hair cells, which leads to glutamateaccumulation, resulting cell death.GRHL2 is a transcription factor which is expressed in different epithelial cells, andresponsible for the maintenance of these cells. GRHL2 gene contributes to epithelial barrierformation and wound healing, closes neutral tube, maintains mucociliary respiratory epitheliumand tumor suppression. In the GRHL2 gene several SNPs have been associated with autosomaldominant, noise induced and age-related hearing loss. MARVELD2 gene associated DFNB49 locus and its mutations causes non-syndromicbilateral, prelingual, moderate or severe deafness. This transmembrane protein is mainlyconcentrated in tricellular tight junctions (tTJ) in the cochlear cells and plays an important rolein forming an epithelial barrier against paracellular flux of ions and solutes, which is essentialto maintain the ion composition of inner ear fluids and proper hearing function. Up to now, sixdeafness causing recessive mutations in this gene have been identified in 15 families worldwide.Several mitochondrial DNA mutations have been associated with hearing loss. Somemutations in the 12S rRNA and tRNA Ser genes of the mitochondrial DNA cause non-syndromic hearing loss, which may be induced by aminoglycoside exposure or developindependent of it. Aminoglycoside-containing antibiotics such as gentamicin, streptomycin andtobramycin are clinically important drugs. The use of these drugs often leads to toxicity,affecting the kidney or the auditory and balancing system. Damage of the kidney is usuallyreversible, but injury of the auditory and balance organs is irreversible. The m.1555A>G andm.1494 T>C mutations in 12SrRNA were identified in patients with aminoglycoside-in-ducedhearing loss. Seven additional mutations in 12S rRNA (m.827 A>G, m.961delTinsC,m.961 T>C, m.961 T>G, m.1005 T>C and m.1095 T>C, m.1116 A>G) have been reported asmitochondrial non-syndromic hearing loss mutations. Although their pathogenic significanceremains contested. A large phenotypic variation is detected in mtDNA-caused hearing loss.Hearing loss may only occur after exposure to aminoglycoside or without it. Furthermore, thedegree of hearing loss alters, even within families. Some mtDNA mutations may not triggerhearing loss on their own, but only in the presence of other environmental or genetic elementsthat modify the variability and penetrance of the hearing loss associated with these mtDNAvariations. These genetic variants can be identified as essential risk factors rather thanpathogenic mutations.