Census of halide-binding sites in protein structures.

MOTIVATION: Halides are negatively charged ions of halogens, forming fluorides (F-), chlorides (Cl-), bromides (Br-) and iodides (I-). These anions are quite reactive and interact both specifically and non-specifically with proteins. Despite their ubiquitous presence and important roles in protein function, little is known about the preferences of halides binding to proteins. To address this problem, we performed the analysis of halide-protein interactions, based on the entries in the Protein Data Bank. RESULTS: We have compiled a pipeline for the quick analysis of halide-binding sites in proteins using the available software. Our analysis revealed that all of halides are strongly attracted by the guanidinium moiety of arginine side chains, however, there are also certain preferences among halides for other partners. Furthermore, there is a certain preference for coordination numbers in the binding sites, with a correlation between coordination numbers and amino acid composition. This pipeline can be used as a tool for the analysis of specific halide-protein interactions and assist phasing experiments relying on halides as anomalous scatters. AVAILABILITY AND IMPLEMENTATION: All data described in this article can be reproduced via complied pipeline published at https://github.com/rostkick/Halide_sites/blob/master/README.md. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Characterization of pathogenic genetic variants in Russian patients with primary ciliary dyskinesia using gene panel sequencing and transcript analysis.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a group of rare genetically heterogeneous disorders caused by defective cilia and flagella motility. The clinical phenotype of PCD patients commonly includes chronic oto-sino-pulmonary disease, infertility, and, in about half of cases, laterality defects due to randomization of left-right body asymmetry. To date, pathogenic variants in more than 50 genes responsible for motile cilia structure and assembly have been reported in such patients. While multiple population-specific mutations have been described in PCD cohorts from different countries, the data on genetic spectrum of PCD in Russian population are still extremely limited. RESULTS: The present study provides a comprehensive clinical and genetic characterization of 21 Russian families with PCD living in various country regions. Anomalies of ciliary beating in patients` respiratory epithelial cells were confirmed by high-speed video microscopy. In the most cases, custom-designed panel sequencing allowed to uncover causative variants in well-known or rarely mentioned PCD-related genes, including DNAH5, DNAH11, CFAP300, LRRC6, ZMYND10, CCDC103, HYDIN, ODAD4, DNAL1, and OFD1. The variations comprised common mutations, as well as novel genetic variants, some of which probably specific for Russian patients. Additional targeted analysis of mRNA transcripts from ciliated cells enabled us to specify functional effects of newly identified genetic variants in DNAH5 (c.2052+3G>T, c.3599-2A>G), HYDIN (c.10949-2A>G, c.1797C>G), and ZMYND10 (c.510+1G>C) on splicing process. In particular, the splice site variant c.2052+3G>T, detected in four unrelated families, resulted in skipping of exon 14 in DNAH5 transcripts and, according to haplotype analysis of affected probands, was proposed as an ancestral founder mutation in Udmurt population. CONCLUSIONS: The reported data provide a vital insight into genetic background of primary ciliary dyskinesia in the Russian population. The findings clearly illustrate the utility of gene panel sequencing coupled with transcriptional analysis in identification and clinical interpretation of novel genetic variants.

The Role of NOTCH Pathway Genes in the Inherited Susceptibility to Aortic Stenosis.

The NOTCH-signaling pathway is responsible for intercellular interactions and cell fate commitment. Recently, NOTCH pathway genes were demonstrated to play an important role in aortic valve development, leading to an increased calcified aortic valve disease (CAVD) later in life. Here, we further investigate the association between genetic variants in the NOTCH pathway genes and aortic stenosis in a case-control study of 90 CAVD cases and 4723 controls using target panel sequencing of full-length 20 genes from a NOTCH-related pathway (DVL2, DTX2, MFNG, NUMBL, LFNG, DVL1, DTX4, APH1A, DTX1, APH1B, NOTCH1, ADAM17, DVL3, NCSTN, DTX3L, ILK, RFNG, DTX3, NOTCH4, PSENEN). We identified a common intronic variant in NOTCH1, protecting against CAVD development (rs3812603), as well as several rare and unique new variants in NOTCH-pathway genes (DTX4, NOTCH1, DTX1, DVL2, NOTCH1, DTX3L, DVL3), with a prominent effect of the protein structure and function.

Complex trait susceptibilities and population diversity in a sample of 4,145 Russians.

The population of Russia consists of more than 150 local ethnicities. The ethnic diversity and geographic origins, which extend from eastern Europe to Asia, make the population uniquely positioned to investigate the shared properties of inherited disease risks between European and Asian ancestries. We present the analysis of genetic and phenotypic data from a cohort of 4,145 individuals collected in three metro areas in western Russia. We show the presence of multiple admixed genetic ancestry clusters spanning from primarily European to Asian and high identity-by-descent sharing with the Finnish population. As a result, there was notable enrichment of Finnish-specific variants in Russia. We illustrate the utility of Russian-descent cohorts for discovery of novel population-specific genetic associations, as well as replication of previously identified associations that were thought to be population-specific in other cohorts. Finally, we provide access to a database of allele frequencies and GWAS results for 464 phenotypes.

Transgenerational and intergenerational effects of early childhood famine exposure in the cohort of offspring of Leningrad Siege survivors.

Famine exposure during early life development can affect disease risk in late-life period, yet, transmission of phenotypic features from famine-exposed individuals to the next generations has not been well characterized. The purpose of our case-control study was to investigate the association of parental starvation in the perinatal period and the period of early childhood with the phenotypic features observed in two generations of descendants of Leningrad siege survivors. We examined 54 children and 30 grandchildren of 58 besieged Leningrad residents who suffered from starvation in early childhood and prenatal age during the Second World War. Controls from the population-based national epidemiological ESSE-RF study (n = 175) were matched on sex, age and body mass index (BMI). Phenotypes of controls and descendants (both generations, children and grandchildren separately) were compared, taking into account multiple testing. Comparison of two generations descendants with corresponding control groups revealed significantly higher creatinine and lower glomerular filtration rate (GFR), both in meta-analysis and in independent analyses. The mean values of GFR for all groups were within the normal range (GFR less than 60 mL/min/1.73 m2 was recorded in 2 controls and no one in DLSS). Additionally, independent of the creatinine level, differences in the eating pattern were detected: insufficient fish and excessive red meat consumption were significantly more frequent in the children of the Leningrad siege survivors compared with controls. Blood pressure, blood lipids and glucose did not differ between the groups. Parental famine exposure in early childhood may contribute to a decrease in kidney filtration capacity and altered eating pattern in the offspring of famine-exposed individuals.

Case Report: Supernormal Vascular Aging in Leningrad Siege Survivors.

Age-related changes in the vascular system play an important role in the biological age and lifespan of a person and maybe affected from an early age onward. One of the indicators of changes in the vascular system is arterial wall stiffness and its main measure, i.e., carotid-femoral pulse wave velocity (cfPWV). We examined arterial wall stiffness in a sample of 305 Leningrad Siege survivors to assess how hunger and stressful conditions during fetal development and early childhood affected the state of the cardiovascular system at a later age and what factors may neutralize the negative impact sustained in early childhood. Here, we presented an evaluation of two unique patients with supernormal vascular aging (SUPERNOVA) phenotype from this cohort and described the details of congruence between hereditary resistance and practiced lifestyle yielding slower biological aging rate.

FTIR Spectroscopy Study of the Secondary Structure Changes in Human Serum Albumin and Trypsin under Neutral Salts.

The effect of neutral salts on protein conformation was first analyzed by Hofmeister in 1888, however, even today this phenomenon is not completely understood. To clarify this effect, we studied changes in the secondary structure of two proteins: human serum albumin with predominantly α-helical structure and porcine pancreas ß-trypsin with the typical ß-structural arrangement in aqueous solutions of neutral salts (KSCN, KCl, (NH4)2SO4). The changes in the secondary structure were studied at 23 °C and 80 °C by using the second derivative deconvolution method of the IR spectra. Our results demonstrated that the ability of the salts to stabilize/destabilize these two proteins correlates with the Hofmeister series of ions. At the same time, some exceptions were also observed. The destabilization of the native structures of both α-helical albumin and ß-structural trypsin upon interaction with neutral salts leads to the formation of intermolecular ß-sheets typical for amyloid fibrils or amorphous aggregates. Thus, our quantitative FTIR-spectroscopy analysis allowed us to further clarify the mechanisms and complexity of the neutral salt actions on protein structures which may lead to strategies preventing unwelcome misfolding of proteins.

Systematic FTIR Spectroscopy Study of the Secondary Structure Changes in Human Serum Albumin under Various Denaturation Conditions.

Human serum albumin (HSA) is the most abundant protein in blood plasma. HSA is involved in the transport of hormones, fatty acids, and some other compounds, maintenance of blood pH, osmotic pressure, and many other functions. Although this protein is well studied, data about its conformational changes upon different denaturation factors are fragmentary and sometimes contradictory. This is especially true for FTIR spectroscopy data interpretation. Here, the effect of various denaturing agents on the structural state of HSA by using FTIR spectroscopy in the aqueous solutions was systematically studied. Our data suggest that the second derivative deconvolution method provides the most consistent interpretation of the obtained IR spectra. The secondary structure changes of HSA were studied depending on the concentration of the denaturing agent during acid, alkaline, and thermal denaturation. In general, the denaturation of HSA in different conditions is accompanied by a decrease in α-helical conformation and an increase in random coil conformation and the intermolecular ß-strands. Meantime, some variation in the conformational changes depending on the type of the denaturation agent were also observed. The increase of ß-structural conformation suggests that HSA may form amyloid-like aggregates upon the denaturation.