Spatial distribution, source apportionment, and assessment of marine water quality parameters in the Bohai Sea, China.

A two-year (2020-2021) survey dataset of six water quality parameters (pH, dissolved oxygen (DO), chemical oxygen demand (COD), dissolved inorganic nitrogen (DIN), soluble reactive phosphate (SRP), and petroleum pollutants) was used to investigate their spatial distribution in the Bohai Sea and quantify their potential sources. There were significant differences in spatial distribution of the parameters. High concentrations of COD, DIN and SRP were found in three bays, with terrestrial input being the main pollution source. Phosphorus-limiting conditions were present in the Bohai Sea. High petroleum pollutant concentrations were identified in port areas, offshore oilfields, and adjacent areas. The pH was above the global oceanic average and there were no signs of acidification. The contribution of the mixed terrestrial inputs, maritime transportation, and offshore oil exploitation sources, oceanic and associated biotic sources, and seawater-atmosphere exchange and atmospheric deposition sources to water quality were 63.4 %, 8.0 %, and 28.6 %, respectively.

Progress in biological activities and biosynthesis of edible fungi terpenoids.

The edible fungi have both edible and medicinal functions, in which terpenoids are one of the most important active ingredients. Terpenoids possess a wide range of biological activities and show great potential in the pharmaceutical and healthcare industries. In this review, the diverse biological activities of edible fungi terpenoids were summarized with emphasis on the mechanism of anti-cancer and anti-inflammation. Subsequently, this review focuses on advances in knowledge and understanding of the biosynthesis of terpenoids in edible fungi, especially in the generation of sesquiterpenes, diterpenes, and triterpenes. This paper is aim to provide an overview of biological functions and biosynthesis developed for utilizing the terpenoids in edible fungi.

Epichloë Endophyte Infection Changes the Root Endosphere Microbial Community Composition of Leymus Chinensis Under Both Potted and Field Growth Conditions.

Epichloë endophytes can not only affect the growth and resistance of the host plant but also change the biotic and abiotic properties of the soil where the host is situated. Here, we used endophyte-infected (EI) and endophyte-free (EF) Leymus chinensis as plant materials, to study the microbial diversity and composition in the host root endosphere and rhizosphere soil under both pot and field conditions. The results showed that endophyte infection did not affect the diversity of either bacteria or fungi in the root zone. There were significant differences in both bacterial and fungal communities between the root endosphere and the rhizosphere, and between the field and the pot, while endophytes only affected root endosphere microbial communities. The bacterial families affected by endophyte infection changed from 29.07% under field conditions to 40% under pot conditions. In contrast, the fungal families affected by endophyte infection were maintained at nearly 50% under both field and pot conditions. That is to say, bacterial communities in the root endosphere were more strongly affected by environmental conditions, and in comparison, the fungal communities were more strongly affected by species specificity. Endophytes significantly affected the fungal community composition of the host root endosphere in both potted and field plants, only the effect was more obvious in potted plants. Endophyte infection increased the abundance of three fungal families (Thelebolaceae, Herpotrichiellaceae and Trimorphomycetaceae) under both field and potted conditions. In potted plants, endophytes also altered the dominant fungi from pathogenic Pleosporales to saprophytic Chaetomiaceae. Endophyte infection increased the relative abundance of arbuscular mycorrhizal fungi and saprophytic fungi, especially under potted conditions.Overall, endophytes significantly affected the fungal community composition of the host root endosphere in both potted and field plants. Endophytes had a greater impact on root endosphere microorganisms than the rhizosphere, a greater impact on fungal communities than bacteria, and a greater impact on root endosphere microorganisms under potted conditions than at field sites.

Epichloë endophytes improved Leymus chinensis tolerance to both neutral and alkali salt stresses.

Symbiotic relationships with microbes may influence how plants respond to environmental change. In the present study, we tested the hypothesis that symbiosis with the endophytes promoted salt tolerance of the native grass. In the field pot experiment we compared the performance of endophyte-infected (E+) and endophyte-uninfected (E-) Leymus chinensis, a dominant species native to the Inner Mongolia steppe, under altered neutral and alkaline salt stresses. The results showed that under both neutral and alkaline salt stresses, endophyte infection significantly increased plant height, leaf length and fibrous root biomass. Under neutral salt stress, endophyte infection decreased Na+ content and Na+/K+ ratio (p=0.066) in the leaf sheath while increased Ca2+ and Mg2+ content in the rhizome. Under alkali salt stress, endophyte infection tended to increase K+ content in the fibrous root, enhance Mg2+ content in the fibrous root while reduce Na+/K+ ratio in the leaf blade in the 100 mmol/L alkali salt treatment. Although endophyte-infected L. chinensis cannot accumulate Na+ high enough to be halophytes, the observed growth promotion and stress tolerance give endophyte/plant associations the potential to be a model for endophyte-assisted phytoremediation of saline-alkaline soils.

Collapsing Focal Segmental Glomerulosclerosis in Siblings With Compound Heterozygous Variants in NUP93 Expand the Spectrum of Kidney Phenotypes Associated With Nucleoporin Gene Mutations.

Background: Focal segmental glomerulosclerosis (FSGS) is a major cause of end stage kidney disease, with the collapsing form having the worst prognosis. Study of families with hereditary FSGS has provided insight into disease mechanisms. Methods: In this report, we describe a sibling pair with NUP93 mutations and collapsing FSGS (cFSGS). For each brother, we performed next generation sequencing and segregation analysis by direct sequencing. To determine if the variants found in the index family are a common cause of cFSGS, we screened 7 patients with cFSGS, gleaned from our cohort of 200 patients with FSGS, for variants in NUP93 as well as for APOL1 high-risk genotypes. Results: We identified segregating compound heterozygous NUP93 variants (1) c.1772G > T p.G591V, 2) c.2084T > C p.L695S) in the two brothers. We did not find any pathogenic variants in the seven patients with cFSGS from our cohort, and as expected five of these seven patients carried the APOL1 high-risk genotype. Conclusion: To the best of our knowledge, this is the first report of cFSGS in patients with NUP93 mutations, based on this report, mutations in NUP93 and other nucleoporin genes should be considered when evaluating a child with familial cFSGS. Determining the mechanisms by which these variants cause cFSGS may provide insight into the pathogenesis of the more common primary and virus-mediated forms of cFSGS.

Polycyclic aromatic hydrocarbons (PAHs) in the Bohai Sea: A review of their distribution, sources, and risks.

The distribution, risks, and sources of polycyclic aromatic hydrocarbons (PAHs) observed in seawater and sediments in the Bohai Sea were reviewed. The ecological risk of total PAHs in seawater was low, but the ecological risks of several individual PAHs (Pyr, BbF, and IcdP) were high. Detected PAHs in sediments rarely had adverse biological effects. High PAH concentrations were identified in Bohai Bay, in the sea area near Qinhuangdao, in Jinzhou Bay, and in Bohai Strait. Low PAH concentrations were found in the central Bohai, in Laizhou Bay, and in the sea area with more intensive ocean currents near Caofeidian. PAH concentrations in the Bohai Sea present a seaward-decreasing trend. Their spatial distribution could be attributed to the influence of human activities (population, industrial activities, and shipping activities), which determined PAH emissions. The PAHs were characterized by local sources, indicating that coal consumption and vehicle emissions were important sources of PAHs. Integr Environ Assess Manag 2022;18:1705-1721. © 2022 SETAC.

Steroid-sensitive nephrotic syndrome candidate gene CLVS1 regulates podocyte oxidative stress and endocytosis.

We performed next-generation sequencing in patients with familial steroid-sensitive nephrotic syndrome (SSNS) and identified a homozygous segregating variant (p.H310Y) in the gene encoding clavesin-1 (CLVS1) in a consanguineous family with 3 affected individuals. Knockdown of the clavesin gene in zebrafish (clvs2) produced edema phenotypes due to disruption of podocyte structure and loss of glomerular filtration barrier integrity that could be rescued by WT CLVS1 but not the p.H310Y variant. Analysis of cultured human podocytes with CRISPR/Cas9-mediated CLVS1 knockout or homozygous H310Y knockin revealed deficits in clathrin-mediated endocytosis and increased susceptibility to apoptosis that could be rescued with corticosteroid treatment, mimicking the steroid responsiveness observed in patients with SSNS. The p.H310Y variant also disrupted binding of clavesin-1 to α-tocopherol transfer protein, resulting in increased reactive oxygen species (ROS) accumulation in CLVS1-deficient podocytes. Treatment of CLVS1-knockout or homozygous H310Y-knockin podocytes with pharmacological ROS inhibitors restored viability to control levels. Taken together, these data identify CLVS1 as a candidate gene for SSNS, provide insight into therapeutic effects of corticosteroids on podocyte cellular dynamics, and add to the growing evidence of the importance of endocytosis and oxidative stress regulation to podocyte function.

Enhancement of carotenoid production and its regulation in edible mushroom Cordyceps militaris by abiotic stresses.

Cordyceps militaris carotenoids are widely used as food additives, animal feed supplements, and so on. However, the biosynthetic pathway of carotenoids in C. militaris is still obscure. In this paper, changes of mycelial morphology and carotenoid accumulation of C. militaris were investigated under oxidative (KMnO4) and osmotic stress (NaCl). Subsequently, qRT-PCR was employed to detect the expression levels of genes related to carotenogenesis to explore the mechanism of adaptation to abiotic stress. When the concentrations of KMnO4 and NaCl were respectively 0.4 g/L and 2 g/L, carotenoid accumulation reached a maximum of 6616.82 ±â€¯666.43 µg/g and 6416.77 ±â€¯537.02 µg/g. Under the oxidative stress condition of KMnO4, the expressions of psy and hsp70 increased significantly compared with control. Besides, the genes fus3 and hog1 were significantly enriched in the MAPK signal pathway. Compared with the control group, there was no significant difference in expression of psy in the NaCl group. Moreover, the accumulation of triacylglycerols may contribute significantly to the increase in carotenoid accumulation. The increased accumulation of antioxidant carotenoids induced under environmental stress is to resist oxidative conditions. Fus3 and Hog1 signaling in the MAPK pathway was activated and subsequently take effects on the resistance of oxidative condition by regulating related metabolic processes. C. militaris resist the stress of high oxygen by producing a large amount of glycerol and carotenoids when this fungus is cultured in a saline environment for a long time.

A Rare Autosomal Dominant Variant in Regulator of Calcineurin Type 1 (RCAN1) Gene Confers Enhanced Calcineurin Activity and May Cause FSGS.

BACKGROUND: Podocyte dysfunction is the main pathologic mechanism driving the development of FSGS and other morphologic types of steroid-resistant nephrotic syndrome (SRNS). Despite significant progress, the genetic causes of most cases of SRNS have yet to be identified. METHODS: Whole-genome sequencing was performed on 320 individuals from 201 families with familial and sporadic NS/FSGS with no pathogenic mutations in any known NS/FSGS genes. RESULTS: Two variants in the gene encoding regulator of calcineurin type 1 (RCAN1) segregate with disease in two families with autosomal dominant FSGS/SRNS. In vitro, loss of RCAN1 reduced human podocyte viability due to increased calcineurin activity. Cells expressing mutant RCAN1 displayed increased calcineurin activity and NFAT activation that resulted in increased susceptibility to apoptosis compared with wild-type RCAN1. Treatment with GSK-3 inhibitors ameliorated this elevated calcineurin activity, suggesting the mutation alters the balance of RCAN1 regulation by GSK-3ß, resulting in dysregulated calcineurin activity and apoptosis. CONCLUSIONS: These data suggest mutations in RCAN1 can cause autosomal dominant FSGS. Despite the widespread use of calcineurin inhibitors in the treatment of NS, genetic mutations in a direct regulator of calcineurin have not been implicated in the etiology of NS/FSGS before this report. The findings highlight the therapeutic potential of targeting RCAN1 regulatory molecules, such as GSK-3ß, in the treatment of FSGS.

Genetic Testing for Steroid-Resistant-Nephrotic Syndrome in an Outbred Population.

Background: Steroid-resistant nephrotic syndrome (SRNS) is a leading cause of end-stage kidney disease in children and young adults. Despite advances in genomic science that have led to the discovery of >50 monogenic causes of SRNS, there are no clear guidelines for genetic testing in clinical practice. Methods: Using high throughput sequencing, we evaluated 492 individuals from 181 families for mutations in 40 known SRNS genes. Causative mutations were defined as missense, truncating, and obligatory splice site variants with a minor allele frequency <1% in controls. Non-synonymous variants were considered pathogenic if determined to be deleterious by at least two in silico models. We further evaluated for differences in age at disease onset, family history of SRNS or chronic kidney disease, race, sex, renal biopsy findings, and extra-renal manifestations in subgroups with and without disease causing variants. Results: We identified causative variants in 40 of 181 families (22.1%) with SRNS. Variants in INF2, COL4A3, and WT1 were the most common, accounting for over half of all causative variants. Causative variants were identified in 34 of 86 families (39.5%) with familial disease and 6 of 95 individuals (6.3%) with sporadic disease (χ2 p < 0.00001). Family history was the only significant clinical predictor of genetic SRNS. Conclusion: We identified causative mutations in almost 40% of all families with hereditary SRNS and 6% of individuals with sporadic disease, making family history the single most important clinical predictors of monogenic SRNS. We recommend genetic testing in all patients with SRNS and a positive family history, but only selective testing in those with sporadic disease.

Trace metals, organic carbon and nutrients in the Beidagang Wetland Nature Reserve, northern China.

This study aimed to determine sediment contamination in the Beidagang Wetland Nature Reserve to describe atmospheric deposition of trace metals. We analyzed Hg, Cd, Pb, TOC, TN, TP, δ13C, and δ15N, and studied their variations in surface sediments and in the vertical profiles of sediment cores collected from the reserve. Evaluation of environmental trace metal contamination using sediment quality guidelines and geochemical background values indicated that the risk of metal pollution in the reserve sediments was relatively low. Concentrations of Hg, Cd, and Pb in the sediments were much lower than concentrations in sediment samples from Bohai Bay and polluted rivers in Tianjin. Enrichment factors indicate that samples are moderately contaminated with Hg, Cd, and Pb; whereas the geo-accumulation index results classify the sediments as uncontaminated to moderately contaminated with Hg, Cd, and Pb. The distribution patterns of trace metal concentrations in the three core samples were uniform. δ13C and δ15N were used to track the sources of TOC and TN in sediments. Results show that TOC mainly originated from the residue and decaying matter of aquatic plants (e.g., algae, reeds, and Typha), while TN was derived from soil N and elevated atmospheric N deposition. Because domestic and industrial waste is not discharged into the Beidagang Wetland Nature Reserve, trace metals found in sediments mainly originate from atmospheric deposition. The results provide baseline data for analysis of trace metal accumulation in Beijing-Tianjin-Hebei, a region subject to atmospheric deposition in northern China.

The Human FSGS-Causing ANLN R431C Mutation Induces Dysregulated PI3K/AKT/mTOR/Rac1 Signaling in Podocytes.

BACKGROUND: We previously reported that mutations in the anillin (ANLN) gene cause familial forms of FSGS. ANLN is an F-actin binding protein that modulates podocyte cell motility and interacts with the phosphoinositide 3-kinase (PI3K) pathway through the slit diaphragm adaptor protein CD2-associated protein (CD2AP). However, it is unclear how the ANLN mutations cause the FSGS phenotype. We hypothesized that the R431C mutation exerts its pathogenic effects by uncoupling ANLN from CD2AP. METHODS: We conducted in vivo complementation assays in zebrafish to determine the effect of the previously identified missense ANLN variants, ANLNR431C and ANLNG618C during development. We also performed in vitro functional assays using human podocyte cell lines stably expressing wild-type ANLN (ANLNWT ) or ANLNR431C . RESULTS: Experiments in anln-deficient zebrafish embryos showed a loss-of-function effect for each ANLN variant. In human podocyte lines, expression of ANLNR431C increased cell migration, proliferation, and apoptosis. Biochemical characterization of ANLNR431C -expressing podocytes revealed hyperactivation of the PI3K/AKT/mTOR/p70S6K/Rac1 signaling axis and activation of mTOR-driven endoplasmic reticulum stress in ANLNR431C -expressing podocytes. Inhibition of mTOR, GSK-3ß, Rac1, or calcineurin ameliorated the effects of ANLNR431C . Additionally, inhibition of the calcineurin/NFAT pathway reduced the expression of endogenous ANLN and mTOR. CONCLUSIONS: The ANLNR431C mutation causes multiple derangements in podocyte function through hyperactivation of PI3K/AKT/mTOR/p70S6K/Rac1 signaling. Our findings suggest that the benefits of calcineurin inhibition in FSGS may be due, in part, to the suppression of ANLN and mTOR. Moreover, these studies illustrate that rational therapeutic targets for familial FSGS can be identified through biochemical characterization of dysregulated podocyte phenotypes.

Removal of cadmium from aqueous solutions using industrial coal fly ash-nZVI.

Batch experiments were conducted to test the effects of various solution properties, such as pH, temperature, initial concentration and anoxic and aerobic atmosphere, on Cd removal by nanoscale zerovalent iron (nZVI) supported on industrial coal fly ash. Cd (II) could be removed by adsorption on fly ash-nZVI in a very short time (5 min) with high removal rates (greater than 99.9%) over a wide range of concentration (5-100 mg l-1). Cd (II) was physically adsorbed on the surface of fly ash-nZVI. The preparation of fly ash-nZVI can incorporate the use of waste media, making the overall adsorbent more removal efficient and low cost.

Dysregulation of WTI (-KTS) is Associated with the Kidney-Specific Effects of the LMX1B R246Q Mutation.

Mutations in the LIM homeobox transcription factor 1-beta (LMX1B) are a cause of nail patellar syndrome, a condition characterized by skeletal changes, glaucoma and focal segmental glomerulosclerosis. Recently, a missense mutation (R246Q) in LMX1B was reported as a cause of glomerular pathologies without extra-renal manifestations, otherwise known as nail patella-like renal disease (NPLRD). We have identified two additional NPLRD families with the R246Q mutation, though the mechanisms by which LMX1BR246Q causes a renal-specific phenotype is unknown. In this study, using human podocyte cell lines overexpressing either myc-LMX1BWT or myc-LMX1BR246Q, we observed dominant negative and haploinsufficiency effects of the mutation on the expression of podocyte genes such as NPHS1, GLEPP1, and WT1. Specifically, we observed a novel LMX1BR246Q-mediated downregulation of WT1(-KTS) isoforms in podocytes. In conclusion, we have shown that the renal-specific phenotype associated with the LMX1BR246Q mutation may be due to a dominant negative effect on WT1(-KTS) isoforms that may cause a disruption of the WT1 (-KTS):(+KTS) isoform ratio and a decrease in the expression of podocyte genes. Full delineation of the LMX1B gene regulon is needed to define its role in maintenance of glomerular filtration barrier integrity.

Trace metal pollution and carbon and nitrogen isotope tracing through the Yongdingxin River estuary in Bohai Bay, Northern China.

A tide gate was built in 2010 to prevent seawater from moving upstream into the Yongdingxin River estuary in Bohai Bay, Northern China. We analysed the concentrations of Hg, Cd, Pb, TOC, TN, δ13C and δ15N and studied their variations in the surface layer and vertical profiles of sediment cores collected from the Yongdingxin River estuary. Contamination factors and geo-accumulation indices were calculated for each metal, which revealed high levels of contamination for Hg and Cd in the sediments, likely from anthropogenic sources. δ13C and δ15N were used as natural tracers to determine the sources of TOC and TN. The results revealed that sewage was the main source of TOC, while TN may have more than one source in the Yongdingxin River estuary. Sewage dominated trace metal pollution in the Yongdingxin River estuary. Our results provide a baseline for trace metal contamination in an estuary facing a large water project.

Rare variants in tenascin genes in a cohort of children with primary vesicoureteric reflux.

BACKGROUND: Primary vesicoureteral reflux (PVUR) is the most common malformation of the kidney and urinary tract, and reflux nephropathy is a major cause of chronic kidney disease in children. Recently, we reported mutations in the tenascin XB gene (TNXB) as a cause of PVUR with joint hypermobility. METHODS: To define the role of rare variants in tenascin genes in the etiology of PVUR, we screened a cohort of patients with familial PVUR (FPVUR) and non-familial PVUR (NFPVUR) for rare missense variants inTNXB and the tenascin C gene (TNC) after excluding mutations in ROBO2 and SOX17. RESULTS: The screening procedure identified 134 individuals from 112 families with PVUR; two families with mutations in ROBO2 were excluded from further analysis. Rare missense variants in TNXB were found in the remaining 110 families, of which 5/55 (9%) families had FPVUR and 2/55 (4%) had NFPVUR. There were no differences in high-grade reflux or renal parenchymal scarring between patients with and without TNXB variants. All patients with TNXB rare variants who were tested exhibited joint hypermobility. Overall we were able to identify causes of FPVUR in 7/57 (12%) families (9% in TNXB and 3% in ROBO2). CONCLUSIONS: In conclusion, the identification of a rare missense variant in TNXB in combination with a positive family history of VUR and joint hypermobility may represent a non-invasive method to diagnose PVUR and warrants further evaluation in other cohorts.

[Spatial distribution of Se in soils from different land use types and its influencing factors within the Yanghe Watershed, China].

Based on different land use types, altitudes, soil and vegetation types etc, 171 representative topsoils (0-10 cm) were collected within the Yanghe watershed, China for determining the total concentrations, spatial distribution and influencing factors of selenium (Se). The results showed that the total selenium concentrations in soils within the watershed ranged from 0.02 to 3.24 mg x kg(-1) dry weight (dw). The geometric mean of Se in soils within the watershed was 0.30 mg x kg(-1), which was higher than those in Beijing plain (0.20 mg x kg(-1)), Hebei plain (0.19 mg x kg(-1)) and China (0.29 mg x kg(-1)). Soils which lacked Se (0.13-0.18 mg x kg(-1)) were mainly distributed in Huaian, Xuanhua, and Huailai counties. Se concentrations in most areas within the watershed were sufficient (0.18-0.45 mg x kg(-1)). In addition, Wanquan, Xinghe, Tianzhen and Yanggao counties also had some selenium-rich areas. Concentrations of Se were different under different land use types. They were of the following order: forest land > industrial and mining land > grassland > agricultural land. Agricultural land had the lowest concentrations of Se, with a mean concentration of 0.28 mg x kg(-1). We also found that parent materials and soil types had no significant effects on soil Se concentrations within the Yanghe Watershed. The results indicated that Se concentrations were positively and significantly correlated with clay contents and altitudes, but negatively and significantly with pH values. Furthermore, TOC, Fe and Al concentrations were also important factors influencing the Se concentrations in soils within the Yanghe Watershed.

A novel missense mutation of Wilms' Tumor 1 causes autosomal dominant FSGS.

FSGS is a clinical disorder characterized by focal scarring of the glomerular capillary tuft, podocyte injury, and nephrotic syndrome. Although idiopathic forms of FSGS predominate, recent insights into the molecular and genetic causes of FSGS have enhanced our understanding of disease pathogenesis. Here, we report a novel missense mutation of the transcriptional regulator Wilms' Tumor 1 (WT1) as the cause of nonsyndromic, autosomal dominant FSGS in two Northern European kindreds from the United States. We performed sequential genome-wide linkage analysis and whole-exome sequencing to evaluate participants from family DUK6524. Subsequently, whole-exome sequencing and direct sequencing were performed on proband DNA from family DUK6975. We identified multiple suggestive loci on chromosomes 6, 11, and 13 in family DUK6524 and identified a segregating missense mutation (R458Q) in WT1 isoform D as the cause of FSGS in this family. The identical mutation was found in family DUK6975. The R458Q mutation was not found in 1600 control chromosomes and was predicted as damaging by in silico simulation. We depleted wt1a in zebrafish embryos and observed glomerular injury and filtration defects, both of which were rescued with wild-type but not mutant human WT1D mRNA. Finally, we explored the subcellular mechanism of the mutation in vitro. WT1(R458Q) overexpression significantly downregulated nephrin and synaptopodin expression, promoted apoptosis in HEK293 cells and impaired focal contact formation in podocytes. Taken together, these data suggest that the WT1(R458Q) mutation alters the regulation of podocyte homeostasis and causes nonsyndromic FSGS.

HLA-DQA1 and PLCG2 Are Candidate Risk Loci for Childhood-Onset Steroid-Sensitive Nephrotic Syndrome.

Steroid-sensitive nephrotic syndrome (SSNS) accounts for >80% of cases of nephrotic syndrome in childhood. However, the etiology and pathogenesis of SSNS remain obscure. Hypothesizing that coding variation may underlie SSNS risk, we conducted an exome array association study of SSNS. We enrolled a discovery set of 363 persons (214 South Asian children with SSNS and 149 controls) and genotyped them using the Illumina HumanExome Beadchip. Four common single nucleotide polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants that were tested (odds ratio, 2.11; 95% confidence interval, 1.56 to 2.86; P=1.68×10(-6) (Fisher exact test). Two of these SNPs-the missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1-were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and ≤589 controls; P=1.42×10(-17)). In the rare variant gene set-based analysis, the best signal was found in PLCG2 (P=7.825×10(-5)). In conclusion, this exome array study identified HLA-DQA1 and PLCG2 missense coding variants as candidate loci for SSNS. The finding of a MHC class II locus underlying SSNS risk suggests a major role for immune response in the pathogenesis of SSNS.

Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes, including inherited genetic defects, with significant proteinuria being the predominant clinical finding at presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome (AS), thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane (GBM) findings. Secondary FSGS is known to develop in classic AS at later stages of the disease. Here, we present seven families with rare or novel variants in COL4A3 or COL4A4 (six with single and one with two heterozygous variants) from a cohort of 70 families with a diagnosis of hereditary FSGS. The predominant clinical finding at diagnosis was proteinuria associated with hematuria. In all seven families, there were individuals with nephrotic-range proteinuria with histologic features of FSGS by light microscopy. In one family, electron microscopy showed thin GBM, but four other families had variable findings inconsistent with classical Alport nephritis. There was no recurrence of disease after kidney transplantation. Families with COL4A3 and COL4A4 variants that segregated with disease represent 10% of our cohort. Thus, COL4A3 and COL4A4 variants should be considered in the interpretation of next-generation sequencing data from such patients. Furthermore, this study illustrates the power of molecular genetic diagnostics in the clarification of renal phenotypes.