"Genetics of hearing loss: etiology, diagnosis, management and the role of gene therapy"

Abstract

The purpose of this dissertation is to describe the genes that cause congenital hearing loss. Congenital hearing loss can be due to either environmental or genetic factors. This dissertation focuses on genetic factors, which with the passage of time and the improvement of living conditions, especially in developed countries, occupy more and more percentages in the occurrence of congenital hearing loss. The genetic causes of hearing loss are estimated to be 68% of cases of hearing loss at birth and 55% of cases of hearing loss at the age of four. Genetic hearing loss is divided into syndromic forms, in which hearing loss is accompanied by at least one clinical symptom and into non-syndromic forms.

The syndromic forms are found in 30% of prelingual hearing loss, while out of the several hundred syndromes, only 30 of them have been found to have the genetic damage that causes them. In non-syndromic, prelingual hearing loss, autosomal recessive heredity is the most common (80%), followed by autosomal dominant (20%), while sex-linked (1%) and mitochondrial (<1%) hearing loss are rarer forms. Hearing loss can also be nongenetic in origin, induced by factors such as perinatal infections, ototoxic drugs, traumas etc. However, many cases are multifactorial, involving a collaboration of exogenous factors and mutations in single genes or several genes. The severity of hearing loss can range from mild hearing loss to deafness while hearing loss can involve all frequencies. 78% of the genes that cause non-syndromic hearing loss are the autosomal recessive genes, of which 50% are due to mutations in the DFNB1 locus and in particular the connexin 26 (GJB2) and connexin 30 (GJB6) genes. The 35delG mutation of the connexin 26 gene represents over 90% of the disease mutations with a carrier frequency of 3.5% -4% in the Greek population. That is, a similar percentage to the frequency of vectors of cystic fibrosis and β-thalassemia. In addition, the combined presence of heterozygous deficiencies of the 309 kb GJB6 cx30 gene and heterozygous GJB2 mutations lead to a corresponding manifestation of the disease.

The mitochondrion has its own DNA, which encodes specific factors that are necessary for the protein synthesis and mitochondrial respiratory chain. Mitochondrial DNA is inherited exclusively through the maternal lineage. Ιn the MITOMAP human mitochondrial genome database are collected mitochondrial mutations. Mitochondrial DNA mutations can involve either small changes to a few bases, the majority of which are point mutations or large rearrangements. Most deficiencies, duplications, inversions or other complex rearrangements involve several mitochondrial genes due to the fact that the mitochondrial genes are very close to each other. Large deficiencies generally remove at least one tRNA gene resulting in translation damage and dysfunction at many points in oxidative phosphorylation and therefore in the energy production process. It is noteworthy that specific mutations in the tRNA genes often cause non-syndromic hearing loss, leaving the other organs intact , which proves that the genotype-phenotype association in mitochondrial diseases is limited. Mitochondrial DNA mutations affect the production of energy in the cell in the form of ATP and many of them are undoubtedly a contributing factor to neurosensory syndromic and non-syndromic hearing loss. The 'hot spots' for hearing loss are the MTRNR1 gene encoding 12S rRNA, the MTTL1 gene encoding tRNA for Leu (UUR) and the MTTS1 gene encoding tRNA for Ser (UCN). At least 5% of prelingual, non-syndromic hearing loss, in Caucasian populations, is due to known mitochondrial mutations, representing the most common cause of hearing loss after the 35delG mutation of the GJB2 nuclear gene encoding make it even bigger. However, it is not clear what percentage of translingual hearing loss due to mitochondrial mutations can be acquired (somatic) or structural.

Conclusions: With this high percentage of mutations in the Greek population, it is proposed to apply prenatal testing for the 35delG mutation of connexin 26, for the mutation of connexin 30, since the mutation of konexin 30 plays a regulatory role in the development of genital herpes even in and mitochondrial mutations such as C1494T and A1555G, due to the fact that they are inherited from the mother. Gene therapy and stem cell therapy are still in the experimental stage with a lot promising results in experimental animals but not yet in humans.

PAPOUTSAKI Eleftheria