Selective Heterozygous Advantage of Carriers of с.-23+1G>A Mutation in GJB2 Gene Causing Autosomal Recessive Deafness 1A.

We present the results of analysis of skin epidermis thickness in individuals with recessive mutation c.-23+1G>A in the GJB2 gene in comparison with individuals without this mutation living in Eastern Siberia (Yakut population). We examined 152 individuals with different genotypes by GJB2 gene mutation c.-23+1G>A. Homozygotes and heterozygotes by c.-23+1G>A have thicker epidermal layer (0.245 mm and 0.269 mm, respectively) in comparison with individuals without this mutation (0.193 mm) (p<0.05). The obtained data support the hypothesis about selective advantage of carriers of mutant GJB2 gene alleles and partly explain extremely high carrier frequency (10.3%) of c.-23+1G>A mutation in the GJB2 gene in Yakut population in Eastern Siberia.

Haplotype Diversity and Reconstruction of Ancestral Haplotype Associated with the c.35delG Mutation in the GJB2 (Cx26) Gene among the Volgo-Ural Populations of Russia.

The mutations in theGJB2(Сх26) gene make the biggest contribution to hereditary hearing loss. The spectrum and prevalence of theGJB2gene mutations are specific to populations of different ethnic origins. For severalGJB2 mutations, their origin from appropriate ancestral founder chromosome was shown, approximate estimations of "age" obtained, and presumable regions of their origin outlined. This work presents the results of the carrier frequencies' analysis of the major (for European countries) mutation c.35delG (GJB2gene) among 2,308 healthy individuals from 18 Eurasian populations of different ethnic origins: Bashkirs, Tatars, Chuvashs, Udmurts, Komi-Permyaks, Mordvins, and Russians (the Volga-Ural region of Russia); Byelorussians, Ukrainians (Eastern Europe); Abkhazians, Avars, Cherkessians, and Ingushes (Caucasus); Kazakhs, Uzbeks, Uighurs (Central Asia); and Yakuts, and Altaians (Siberia). The prevalence of the c.35delG mutation in the studied ethnic groups may act as additional evidence for a prospective role of the founder effect in the origin and distribution of this mutation in various populations worldwide. The haplotype analysis of chromosomes with the c.35delG mutation in patients with nonsyndromic sensorineural hearing loss (N=112) and in population samples (N =358) permitted the reconstruction of an ancestral haplotype with this mutation, established the common origin of the majority of the studied mutant chromosomes, and provided the estimated time of the c.35delG mutation carriers expansion (11,800 years) on the territory of the Volga-Ural region.

[Analysis of mitochondrial 12S rRNA and tRNA(Ser(UCN)) genes in patients with nonsyndromic sensorineural hearing loss from various regions of Russia].

Mitochondrial DNA (mtDNA) mutations play an important role in etiology of hereditary hearing loss. In various regions of the world, patients suffer from nonsyndromic sensorineural hearing loss initiated by aminoglycoside antibiotics. Mutations that had been shown as pathogenetically important for hearing function disturbance were identified in mitochondrial 12S rRNA and tRNA(Ser(UCN)) genes while pathogenic role of several DNA sequences requires additional studies. This work presents the results of studying the spectrum of mutations and polymorphic variations in mtDNA genes 12S rRNA and tRNA(Ser(UGN)) in 410 patients with nonsyndromal sensoneural hearing impairment/loss from the Volga Ural region, St Petersburg, Yakutia, and Altai and in 520 individuals with normal hearing, which represent several ethnic groups (Russians, Tatars, Bashkirs, Yakuts, Altaians) residing in the Russian Federation. Pathogenetically significant mutation A1555G (12S rRNA) was found in two families (from Yakutia and St Peresburg) with hearing loss, probably caused by treatment with aminoglucosides, and in the population sample of Yakuts with a frequency of 0.83%. Further research is needed to confirm the role in hearing impairment of mutations 961insC, 961insC(n), 961delTinsC(n), T961G, T1095C (12S rRNA) and G7444A, A7445C (tRNA(Ser(UGN revealed in the patients. In addition, in the patients and the population groups, polymorphic mt DNA variants were detected, which are characteristic also of other Eurasian populations both in spectrum and frequency.

[Cochlear implantation in a child with congenital sensorineural deafness due to 35 DELG mutation in GJB2 (connexin 26) gene].

This paper reports the first case of cochlear implantation performed in this country in a child with congenital non-syndromic sensorineural loss of hearing having hereditary etiology and attributable to autosomal-recessive 35 delG mutation in locus DFNB1 (13q.11-q12) of GJB2 (connexin 26) gene.

[Connexin gene 26 (GJB2) mutations in patients with hereditary non-syndromic sensorineural loss of hearing in the Republic of Sakha (Yakutia)].

The aim of the study was to elucidate the causes of hereditary non-syndromic loss of hearing, a frequent monogene pathology in the Republic of Sakha (Yakutia). A search for mutations in the coding sequence of the connexin 26 gene gap-junction B2 (GJB2) was undertaken in 79 members of 65 unrelated families with the diagnosis of grade III-IV non-syndromic bilateral sensorineural loss of hearing. Five recessive mutations (35delG, V371, 312-326del14, 333-334delAA, R127H) and three polymorphic variants (V271, M34T, E114G) were identified in Yakut patients. Mutations 35delG (41.7%), 312-326dell4 (4.2%), and 333-334delAA (4.2%) were found in Caucasian patients (Russians, Ukrainians, Inguish). Yakuts were carriers of mutations 35delG (2.1%), V371 (2.1%), R127H (1.0%) and sequence variants V271 (6.3%), M34T (1.0%), E114G (1.0%). GJB2 mutations were identified in 50.1% of the Caucasian patients and in 7.2% of the Yakut patients. The low frequency of GJB2 mutations in Yakuts with non-syndromic sensorineural loss of hearing testifies to the presence of mutations of other genes controlling sound perception in this population.

[Molecular genetics of Usher syndrome].

Usher syndrome (USH) is inherited in an autosomal recessive mode. The disease is characterized by hearing loss, progressing vision loss, and vestibular dysfunction. In most cases, it is the reason for deafness and blindness in school-age children. The prevalence of USH in the main population is estimated as 4.4 per 100,000 individuals, approximately. The prevalence of heterozygous carriers can reach 1 per 70 normally hearing individuals. There is currently no effective treatment of USH. The patients are provided with hearing aids, but, in case of severe hearing impairement these aids give no effect. In view of this, developing diagnostic methods is important. It is believed that molecular genetic investigations will enable early diagnostics of the syndrome.

[Molecular-genetic basis of tapetoretinal degeneration].

The review on problem tapetoretinal degeneration (TD) which represents serious enough and incurable disease revealed with frequency 1 : 3500-5000 in general population is presented. The most often reason of occurrence TD are mutations in RHO, RDS and RPE65 genes. The precise interrelation of pigmentary degenerations of a retina and mutations in genes RHO, RDS and RPE65 will allow to develop approaches of DNA--diagnostics of hereditary dystrophies of a retina so frequently meeting in clinical practice of the ordinary ophthalmologist, and also to pass at medical genetics consultation from probability estimations of risk of disease to unequivocal. Also the molecular analysis of genes changes in the providing correct functioning of photoreceptors and pigmentary epithelium of a retina and determining pathological changes at TD, will allow to approach to understanding of the physiological and pathological processes proceeding in a retina and by that will serve becoming and development pathogenic to caused therapy TD closer.

[Genes of connexin proteins participating in sound perception].

Congenital deafness is a severe, incurable and hardly correctable inherited disease. Mutations in GCB2 and GJB6 genes are most prevalent causes of deafness and occur in patients with hereditary and sporadic deafness all over the world. Some ethnic groups exhibit high rate of heterozygous carriage of most frequent GJB2 mutations (35delG, 167delT, 235delC). Definite association of hereditary deafness and mutational alterations in genes of connexins 26, 30 and 31 shows high informative value of molecular-genetic methods which diagnose hereditary deafness, carriage of mutations in GJB2, GJB3 and GJB6 genes, provide definite probability of the disease in medico-genetic consulting. Further progress in genetics of hereditary hearing loss will raise efficacy of deafness diagnosis at early stages of fetal development and prevent birth of babies with congenital defects of sound perception.