A common founder effect of the splice site variant c.-23 + 1G > A in GJB2 gene causing autosomal recessive deafness 1A (DFNB1A) in Eurasia.

Mutations in the GJB2 gene are known to be a major cause of autosomal recessive deafness 1A (OMIM 220290). The most common pathogenic variants of the GJB2 gene have a high ethno-geographic specificity in their distribution, being attributed to a founder effect related to the Neolithic migration routes of Homo sapiens. The c.-23 + 1G > A splice site variant is frequently found among deaf patients of both Caucasian and Asian origins. It is currently unknown whether the spread of this mutation across Eurasia is a result of the founder effect or if it could have multiple local centers of origin. To determine the origin of c.-23 + 1G > A, we reconstructed haplotypes by genotyping SNPs on an Illumina OmniExpress 730 K platform of 23 deaf individuals homozygous for this variant from different populations of Eurasia. The analyses revealed the presence of common regions of homozygosity in different individual genomes in the sample. These data support the hypothesis of the common founder effect in the distribution of the c.-23 + 1G > A variant of the GJB2 gene. Based on the published data on the c.-23 + 1G > A prevalence among 16,177 deaf people and the calculation of the TMRCA of the modified f2-haplotypes carrying this variant, we reconstructed the potential migration routes of the carriers of this mutation around the world. This analysis indicates that the c.-23 + 1G > A variant in the GJB2 gene may have originated approximately 6000 years ago in the territory of the Caucasus or the Middle East then spread throughout Europe, South and Central Asia and other regions of the world.

Oral in vivo bactofection in dextran sulfate sodium treated female Wistar rats.

Salmonella typhimurium SL7207 carrying Cu-Zn superoxide dismutase and an N-terminal deletion mutant of monocyte chemoattractant protein-1 genes was applied to dextran sodium sulfate treated female Wistar rats. Stool quality, food and water intake were monitored. Markers of oxidative stress, interleukin 1, interleukin 6 and tumor necrosis factor alpha were quantified. No differences were found in body weights, markers of oxidative stress in plasma and inflammatory markers in colon homogenates. Plasma concentrations of I11, I16 were lower in the treatment groups than in the dextran sodium sulfate group. However, dextran sodium sulfate induced inflammation could not be confirmed by plasma levels of I11, I16 and TNFalpha. Although some parameters showed a tendency to improve, the inflammation caused by administration of 4% dextran sodium sulfate during 7 days was low and contradictory to other studies. Results showed the potential synergic effect of combined bacteria-mediated antioxidative and anti-inflammatory gene therapy.

Mutation analysis of the CFTR gene in Slovak cystic fibrosis patients by DHPLC and subsequent sequencing: identification of four novel mutations.

Cystic fibrosis (CF) is the most common lethal autosomal recessive disorder in Caucasians. Its incidence is approximately 1:2500 newborns. CF is caused by mutations in the transmembrane conductance regulator (CFTR) gene, which encodes an important chloride ion channel. The disease affects the respiratory, digestive and reproductive systems. To date more than 1550 mutations and polymorphisms have been identified throughout the CFTR gene, making the DNA diagnosis more difficult. Rapid accurate identification of CFTR gene mutations is important for confirming the clinical diagnosis, for cascade screening in families at risk for CF, for understanding the correlation between genotype and phenotype, and moreover it is also the only means for prenatal diagnosis. Individuals suspect of CF are in Slovakia presently screened for the presence of 30 common mutations, giving mutation detection rate only approximately 48%. To increase the detection rate we applied a gene scanning approach using DHPLC system for analysing specifically all CFTR exons. The fragments showing abnormal elution profiles were subsequently sequenced to characterize the DNA change. We have identified a total of 28 different mutations up to present not found in Slovak CF patients, and 17 different polymorphisms. Four mutations (G437D, H954P, H1375N, and 3120+33G>T) are novel, not yet found in any other CF patient all over the word.