Analysis of Polymorphism of Uniparental Markers in Reindeer-Herding Populations: The Tozhu Tuvans of Russia and The Tsaatans Of Mongolia

We analyzed the data on the variability of the Y chromosome and mitochondrial DNA (mtDNA) in populations of the Tsaatans of Mongolia and the Tozhu Tuvans of Russia. The populations studied are characterized by low genetic diver¬sity for both marker systems. The analysis of Y chromosome haplogroups in the Tsaatan and Tozhu revealed three hap¬logroups in the Tsaatan and seven haplogroups in the Tozhu. The composition of the haplogroups is coherent to literature data on the Tuvans, which is explained by common origin. According to the data on mitochondrial DNA variability, 12 haplogroups were determined in 46 Tozhus, of which C4b (30.43%) and F1b1b (23.91%) are major haplogroups. According to the HVS–1 (HyperVariable Segment) data, 15 haplotypes were found in the Tozhu Tuvans and the diversity coefficient of 0.8677 turned out to be much lower than among the Torghut of Mongolia (0.9857). In 23 Tsaatans, 14 haplogroups were determined; the most common of which are C4b (22.73%) and C5a1 (18.18%). According to HVS-1, 14 haplotypes were revealed in the Tsaatan, the diversity is 0.9486. The data obtained on uniparental marker systems in the Tozhus and Tsaatans are due to the isolated and inaccessible taiga region and the manifestation of the “founder effect”. The Tsaatans are less polymorphic in terms of the variety of Y chromosome haplogroups, while the Tozhus are less polymorphic in terms of mitochondrial DNA, which is probably a consequence of a high rate of endogamic marriages in the populations studied

Burkholderia cepacia in cystic fibrosis children and adolescents: overall survival and immune alterations

BackgroundIn current literature there are only scarce data on the host inflammatory response during Burkholderia cepacia complex (Bcc) persistence. The primary objective of the present research was to carry out cross-sectional analyses of biomarkers and evaluate disease progression in cystic fibrosis (CF) patients with chronic Bcc infection and pathogen-free ones. The secondary aim was to assess prospectively overall survival of the study participants during up to 8 years of follow-up.MethodsThe study included 116 paediatric patients with CF; 47 CF patients were chronically infected with Bcc, and 69 individuals were Bcc free. Plasma and sputum biomarkers (neutrophil elastase, MMP-8, MMP-9, MMP-12, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, IL-22, IL-23, IL-17, IFN-γ, TGFβ1, TNF-α) were analysed using commercially available kits. Besides, inhibitory effect of dexamethasone on proliferative response of PHA-stimulated peripheral blood lymphocytes had been assessed.ResultsBcc infected patients did not differ from Bcc free ones in demographic and clinical parameters, but demonstrated an increased rate of glucose metabolism disturbances and survival disadvantage during prolong follow-up period. Biomarkers analyses revealed elevated TNF-α and reduced IL-17F levels in sputum samples of Bcc infected patients. These patients also demonstrated improvement of peripheral blood lymphocyte sensitivity to steroid treatment and reduction in plasma pro-inflammatory (IL-17F and IL-18) and anti-inflammatory (TGFβ1 and IL-10) cytokine concentrations.ConclusionsReduction in IL-17F levels may have several important consequences including increase in steroid sensitivity and glycemic control disturbances. Further investigations are needed to clarify the role of IL-17 cytokines in CF complication development. Low plasma TGFβ1 and IL-10 levels in Bcc infected group may be a sign of subverted activity of regulatory T cells. Such immune alterations may be one of the factors contributing to the development of the cepacia syndrome

Relative Frequencies of PAX6 Mutational Events in a Russian Cohort of Aniridia Patients in Comparison with the World’s Population and the Human Genome

Genome-wide sequencing metadata allows researchers to infer bias in the relative frequencies of mutational events and to predict putative mutagenic models. In addition, much less data could be useful in the evaluation of the mutational frequency spectrum and the prevalent local mutagenic process. Here we analyzed the PAX6 gene locus for mutational spectra obtained in our own and previous studies and compared them with data on other genes as well as the whole human genome. MLPA and Sanger sequencing were used for mutation searching in a cohort of 199 index patients from Russia with aniridia and aniridia-related phenotypes. The relative frequencies of different categories of PAX6 mutations were consistent with those previously reported by other researchers. The ratio between substitutions, small indels, and chromosome deletions in the 11p13 locus was within the interval previously published for 20 disease associated genomic loci, but corresponded to a higher end due to very high frequencies of small indels and chromosome deletions. The ratio between substitutions, small indels, and chromosome deletions for disease associated genes, including the PAX6 gene as well as the share of PAX6 missense mutations, differed considerably from those typical for the whole genome

High carrier frequency of a nonsense p.Trp230* variant in HSD3B2 gene in Ossetians

BackgroundCongenital adrenal hyperplasia (CAH) caused by 3β-HSD deficiency is a rare form of congenital adrenal deficiency with an autosomal recessive type of inheritance. Previously we have demonstrated that a single nucleotide variant (SNV) p.Trp230* in the homozygous state is a frequent cause of CAH among the indigenous population of North Ossetia-Alania represented by Ossetians.MethodsGenotyping of the NM_000198.3:c.690G>A p.Trp230* variant was performed by Real-time PCR. 339 healthy individuals of Ossetian origin were included in the study. Allele frequencies, Fisher’s confidence intervals (CI) were calculated using the WinPepi v. 11.65 software. Comparison of allele frequencies was performed with the z-score test for two proportions.ResultsEight heterozygous carriers of c.690G>A variant in HSD3B2 gene were detected in 339 samples investigated. The total allele frequency of p.Trp230* variant was 0.0118 (n=8/678, 95% CI=0.0051–0.0231). Accordingly, the heterozygous carrier rate was 0.0236 (n=8/339). The frequency of CAH caused by p.Trp230* variant in HSD3B2 in Ossetian population was 1:7183 or 13.9 per 100,000 (95% CI: 1:1874–1:38447 or 3–53 per 100,000).ConclusionThe results demonstrate high frequency of p.Trp230* variant in Ossetians, which is most likely attributed to a founder effect

Hereditary etiology of non-syndromic sensorineural hearing loss in the Republic of North Ossetia–Alania

More than 50% of congenital hearing loss is hereditary, in which the majority form is non-syndromic. In this study we estimate the most prevalent pathogenic genetic changes in an Ossetian cohort of patients. This is useful for local public health officials to promote genetic counseling of affected families with regard to high allele frequencies of prevalent pathogenic variants and assortative mating in the community of people with hearing loss. In this study, genetic heterogeneity of hereditary non-syndromic sensorineural hearing loss (NSNHL) in a cohort of 109 patients and an assessment of the frequency of two GJB2 gene pathogenic variants in a cohort of 349 healthy individuals from the populations of the Republic of North Ossetia–Alania (RNO–Alania) were assessed. The molecular genetic cause of NSNHL in the GJB2 gene in RNO–Alania was confirmed in ~30% of the cases, including ~27% in Ossetians. In Russian patients, the most frequent variant is GJB2:c.35delG (~83%). The GJB2:c.358_360delGAG variant was found to be the most frequent among Ossetians (~54%). Two genetic variants in GJB2, c.35delG and c.358_360delGAG, accounted for 91% of GJB2 pathogenic alleles in the Ossetian patients. A search for large genome rearrangements revealed etiological cause in two Ossetian patients, a deletion at the POU3F4 gene locus associated with X-linked hearing loss (type DFNX2). In another Ossetian patient, a biallelic pathogenic variant in the MYO15A gene caused hearing loss type DFNB3 was identified, and in one Russian family a heterozygous MYH14 gene variant associated with dominant NSNHL was found. Thus, the informative value of the diagnosis was ~37% among all patients with NSNHL from RNO–Alania and ~32% among the Ossetians. These estimates correspond to the literature data on the fraction of recessive genetic forms of hearing loss within the affected population. The importance of this study consists not only in the estimation of the most prevalent pathogenic genetic changes in the Ossetian cohort of patients which could be useful for the public health but also in the genetic counselling of the affected families with regard to the high allele frequencies of revealed pathogenic variants as well as to the assortative mating in community of people with hearing loss

Genetic Variant c.245A>G (p.Asn82Ser) in GIPC3 Gene Is a Frequent Cause of Hereditary Nonsyndromic Sensorineural Hearing Loss in Chuvash Population

Hereditary nonsyndromic sensorineural hearing loss is a disease in which hearing loss occurs due to damage to the organ of the inner ear, the auditory nerve, or the center in the brain that is responsible for the perception of sound, characterized by wide locus and allelic heterogeneity and different types of inheritance. Given the diversity of population of the Russian Federation, it seems necessary to study the ethnic characteristics of the molecular causes of the disease. The aim is to study the molecular and genetic causes of hereditary sensorineural hearing loss in Chuvash, the fifth largest ethnic group in Russia. DNA samples of 26 patients from 21 unrelated Chuvash families from the Republic of Chuvashia, in whom the diagnosis of hereditary sensorineural hearing loss had been established, were analyzed using a combination of targeted Sanger sequencing, multiplex ligase-dependent probe amplification, and whole exome sequencing. The homozygous variant NM_133261.3(GIPC3):c.245A>G (p.Asn82Ser) is the major molecular cause of hereditary sensorineural hearing loss in 23% of Chuvash patients (OMIM #601869). Its frequency was 25% in patients and 1.1% in healthy Chuvash population. Genotyping of the NM_133261.3(GIPC3):c.245A>G (p.Asn82Ser) variant in five neighboring populations from the Volga-Ural region (Russian, Udmurt, Mary, Tatar, Bushkir) found no evidence that this variant is common in those populations

Molecular-genetic causes for the high frequency of phenylketonuria in the population from the North Caucasus

<div><p>Phenylketonuria is an inherited disease caused by mutations in the phenylalanine hydroxylase gene <i>PAH</i>. Different <i>PAH</i> pathogenic variants occur in different ethnic groups with various frequencies and the incidence of the disease itself varies from country to country. In the Caucasus region of Russia, some ethnoses are geographically and culturally isolated from each other. The tradition of monoethnic marriages may cause decreased genetic variability in those populations. In the Karachay-Cherkess Republic (Russia), the highest incidence of phenylketonuria in the world has been detected (1:850 newborns) in the region and 1:332 among the titular nation Karachays. Here, we showed that this phenomenon is due to the widespread prevalence of the p.Arg261* variant. Its allele frequency among Karachay patients with PKU was 68.4% and the carrier frequency in Karachays was 1:16 healthy individuals. <i>PAH</i> haplotype analysis showed a unique common origin. The founder haplotype and mutation “age” were estimated by analyzing the linkage disequilibrium between p.Arg261* and extragenic short tandem repeat loci. The p.Arg261* variant occurred in the Karachays population 10.2 ± 2.7 generations ago (275 ± 73 years) and its spread occurred in parallel with the growth of the population.</p></div

Karachay population dynamics from 1790 to 2010.

<p>The dots indicate the population numbers of the Karachay population [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0201489#pone.0201489.ref027" target="_blank">27</a>]. The curve is the approximation of exponential dependence on the graph of abundance versus time. The point of p.Arg261* origin is marked by an arrow; the error interval is in a square.</p

Survey data of healthy KCR residents.

<p>Survey data of healthy KCR residents.</p

Comprehensive Assessment of <i>CFTR</i> Modulators’ Therapeutic Efficiency for N1303K Variant

p.Asn1303Lys (N1303K) is a common missense variant of the CFTR gene, causing cystic fibrosis (CF). In this study, we initially evaluated the influence of CFTR modulators on the restoration of N1303K-CFTR function using intestinal organoids derived from four CF patients expressing the N1303K variant. The forskolin-induced swelling assay in organoids offered valuable insights about the beneficial effects of VX-770 + VX-661 + VX-445 (Elexacaftor + Tezacaftor + Ivacaftor, ETI) on N1303K-CFTR function restoration and about discouraging the prescription of VX-770 + VX-809 (Ivacaftor + Lumacaftor) or VX-770 + VX-661 (Ivacaftor + Tezacaftor) therapy for N1303K/class I patients. Then, a comprehensive assessment was conducted on an example of one patient with the N1303K/class I genotype to examine the ETI effect on the restoration of N1303K-CFTR function using in vitro the patient’s intestinal organoids, ex vivo the intestinal current measurements (ICM) method and assessment of the clinical status before and after targeted therapy. All obtained results are consistent with each other and have proven the effectiveness of ETI for the N1303K variant. ETI produced a significant positive effect on forskolin-induced swelling in N1303K/class I organoids indicating functional improvement of the CFTR protein; ICM demonstrated that ETI therapy restored CFTR function in the intestinal epithelium after three months of treatment, and the patient improved his clinical status and lung function, increased his body mass index (BMI) and reduced the lung pathogenic flora diversity, surprisingly without improving the sweat test results