APOL1 at 10 years: progress and next steps Freedman, Barry I.; Kopp, Jeffrey B.; Sampson, Matthew G. ...
Kidney international,
06/2021, Letnik:
99, Številka:
6
Journal Article
Recenzirano
Odprti dostop
APOL1 kidney risk variants (RVs) were identified in 2010 as major drivers of glomerular, tubulointerstitial, and renal microvascular disease in individuals with sub-Saharan African ancestry. In ...December 2020, the “APOL1 at Ten” conference summarized the first decade of progress and discussed controversies and uncertainties that remain to be addressed. Topics included trypanosome infection and its role in the evolution of APOL1 kidney RVs, clinical phenotypes in APOL1-associated nephropathy, relationships between APOL1 RVs and background haplotypes on cell injury and molecular mechanisms initiating disease, the role of clinical APOL1 genotyping, and development of novel therapies for kidney disease. Future goals were defined, including improved characterization of various APOL1 RV phenotypes in patients and experimental preclinical models; further dissection of APOL1-mediated pathways to cellular injury and dysfunction in kidney (and other) cells; clarification of gene-gene and gene-environment interactions; and evaluation of the role for existing and novel therapies.
A method to estimate objectively the surface wind fields associated with tropical cyclones using only data from multiple satellite platforms and satellite-based wind retrieval techniques is ...described. The analyses are computed on a polar grid using a variational data-fitting method that allows for the application of variable data weights to input data. The combination of gross quality control and the weighted variational analysis also produces wind estimates that have generally smaller errors than do the raw input data. The resulting surface winds compare well to the NOAA Hurricane Research Division H*Wind aircraft reconnaissance–based surface wind analyses, and operationally important wind radii estimated from these wind fields are shown to be generally more accurate than those based on climatological data. Most important, the analysis system produces global tropical cyclone surface wind analyses and related products every 6 h—without aircraft reconnaissance data. Also, the analysis and products are available in time for consideration by forecasters at the Joint Typhoon Warning Center, the Central Pacific Hurricane Center, and the National Hurricane Center in preparing their forecasts and advisories. This Multiplatform Tropical Cyclone Surface Wind Analysis (MTCSWA) product is slated to become an operationally supported product at the National Environmental Satellite Data and Information Service (NESDIS). The input data, analysis method, products, and verification statistics associated with the MTCSWA are discussed within.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Dielectric permittivities for HFOs R1234yf & R1234ze(E) measured with a re-entrant resonator.•Data range from 248 to 365 K at pressures to 11 MPa for both gas and liquid phases.•Correlations that ...represent measured permittivities within 0.05 over entire range are presented.•Measured dipole moments about 12% smaller than predicted by molecular modelling.•Significant molecular ordering in liquid phase inferred from Kirkwood g factors.
Dielectric permittivities (εr) have been measured using a microwave re-entrant resonator at temperatures from (248 to 365) K and pressures up to 11 MPa for the alternative refrigerants 1,3,3,3-tetrafluoropropene (R1234ze(E)) and 2,3,3,3-tetrafluoropropene (R1234yf) in the liquid and vapour phases. Values of εr were also measured for liquid CO2 at temperatures below 274 K, extending the data available for this fluid. Molecular polarizability, dipole moment, and the dielectric virial coefficients of each hydrofluoroolefin (HFO) refrigerant were determined by applying the dielectric virial expansion and Kirkwood equation to the measured permittivity data. The experimental results for the vapour phase lead to dipole moments with relative standard uncertainties around 5% that are in reasonable agreement with values from molecular modelling. The measured dipole moment for R1234ze(E) of 1.13 D is about 12% smaller than predicted, while the measured dipole moment for R1234yf of 2.24 D is about 11% smaller than predicted. In the compressed liquid region, the two refrigerants exhibited quite different dependencies on temperature and density. The polarizability of liquid R1234ze(E) could be predicted within 4.2% using the gas phase parameters (measured dipole moment and molecular polarizability). In contrast, the temperature dependence of the polarizability of R1234yf was twice as large in the liquid phase as in the gas phase. The density dependence of the polarizability for liquid R1234yf is at least 10 times that of liquid R1234ze(E). Liquid phase data were also used to estimate effective Kirkwood correlation factors, g, by assuming them to be temperature independent over the range of measurements. The results indicate g ≈ 2.4 for R1234yf and g ≈ 1.2 for R1234ze(E).
UBD modifies APOL1-induced kidney disease risk Zhang, Jia-Yue; Wang, Minxian; Tian, Lei ...
Proceedings of the National Academy of Sciences - PNAS,
03/2018, Letnik:
115, Številka:
13
Journal Article
Recenzirano
Odprti dostop
People of recent African ancestry develop kidney disease at much higher rates than most other groups. Two specific coding variants in the Apolipoprotein-L1 gene APOL1 termed G1 and G2 are the causal ...drivers of much of this difference in risk, following a recessive pattern of inheritance. However, most individuals with a high-risk APOL1 genotype do not develop overt kidney disease, prompting interest in identifying those factors that interact with APOL1. We performed an admixture mapping study to identify genetic modifiers of APOL1-associated kidney disease. Individuals with two APOL1 risk alleles and focal segmental glomerulosclerosis (FSGS) have significantly increased African ancestry at the UBD (also known as FAT10) locus. UBD is a ubiquitin-like protein modifier that targets proteins for proteasomal degradation. African ancestry at the UBD locus correlates with lower levels of UBD expression. In cell-based experiments, the disease-associated APOL1 alleles (known as G1 and G2) lead to increased abundance of UBD mRNA but to decreased levels of UBD protein. UBD gene expression inversely correlates with G1 and G2 APOL1-mediated cell toxicity, as well as with levels of G1 and G2 APOL1 protein in cells. These studies support a model whereby inflammatory stimuli up-regulate both UBD and APOL1, which interact in a functionally important manner. UBD appears to mitigate APOL1-mediated toxicity by targeting it for destruction. Thus, genetically encoded differences in UBD and UBD expression appear to modify the APOL1-associated kidney phenotype.
Collapsing glomerulopathy (CG) is most often associated with fast progression to kidney failure with an incidence apparently higher in Brazil than in other countries. However, the reason for this ...occurrence is unknown. To better understand this, we performed an integrated analysis of clinical, histological, therapeutic, causative genetic and genetic ancestry data in a highly genetically admixed cohort of 70 children and adult patients with idiopathic CG (ICG). The disease onset occurred at 23 (interquartile range: 17-31) years and approximately half of patients progressed to chronic kidney disease requiring kidney replacement therapy (CKD-KRT) 36 months after diagnosis. Causative genetic bases, assessed by targeted-gene panel or whole-exome sequencing, were identified in 58.6% of patients. Among these cases, 80.5% harbored APOL1 high-risk genotypes (HRG) and 19.5% causative Mendelian variants (MV). Self-reported non-White patients more frequently had HRG. MV was an independent risk factor for progression to CKD-KRT by 36 months and the end of follow-up, while remission was an independent protective factor. All patients with HRG manifested CG at 9-44 years of age, whereas in those with APOL1 low-risk genotype, the disease arose throughout life. HRGs were associated with higher proportion of African genetic ancestry. Novel causative MVs were identified in COL4A5, COQ2 and PLCE1 and previously described causative MVs were identified in MYH9, TRPC6, COQ2, COL4A3 and TTC21B. Three patients displayed HRG combined with a variant of uncertain significance (ITGB4, LAMA5 or PTPRO). MVs were associated with worse kidney prognosis. Thus, our data reveal that the genetic status plays a major role in ICG pathogenesis, accounting for more than half of cases in a highly admixed Brazilian population.
Display omitted
Chromatin accessibility assays are central to the genome-wide identification of gene regulatory elements associated with transcriptional regulation. However, the data have highly variable quality ...arising from several biological and technical factors. To surmount this problem, we developed a sequence-based machine learning method to evaluate and refine chromatin accessibility data. Our framework, gapped k-mer SVM quality check (gkmQC), provides the quality metrics for a sample based on the prediction accuracy of the trained models. We tested 886 DNase-seq samples from the ENCODE/Roadmap projects to demonstrate that gkmQC can effectively identify "high-quality" (HQ) samples with low conventional quality scores owing to marginal read depths. Peaks identified in HQ samples are more accurately aligned at functional regulatory elements, show greater enrichment of regulatory elements harboring functional variants, and explain greater heritability of phenotypes from their relevant tissues. Moreover, gkmQC can optimize the peak-calling threshold to identify additional peaks, especially for rare cell types in single-cell chromatin accessibility data.
Hypophosphatemic rickets (HR) is a heterogeneous genetic phosphate wasting disorder. The disease is most commonly caused by mutations in the PHEX gene located on the X-chromosome or by mutations in ...CLCN5, DMP1, ENPP1, FGF23, and SLC34A3. The aims of this study were to perform molecular diagnostics for four patients with HR of Indian origin (two independent families) and to describe their clinical features.
We performed whole exome sequencing (WES) for the affected mother of two boys who also displayed the typical features of HR, including bone malformations and phosphate wasting. B-lymphoblast cell lines were established by EBV transformation and subsequent RT-PCR to investigate an uncommon splice site variant found by WES. An in silico analysis was done to obtain accurate nucleotide frequency occurrences of consensus splice positions other than the canonical sites of all human exons. Additionally, we applied direct Sanger sequencing for all exons and exon/intron boundaries of the PHEX gene for an affected girl from an independent second Indian family.
WES revealed a novel PHEX splice acceptor mutation in intron 9 (c.1080-3C>A) in a family with 3 affected individuals with HR. The effect on splicing of this mutation was further investigated by RT-PCR using RNA obtained from a patient's EBV-transformed lymphoblast cell line. RT-PCR revealed an aberrant splice transcript skipping exons 10-14 which was not observed in control samples, confirming the diagnosis of X-linked dominant hypophosphatemia (XLH). The in silico analysis of all human splice sites adjacent to all 327,293 exons across 81,814 transcripts among 20,345 human genes revealed that cytosine is, with 64.3%, the most frequent nucleobase at the minus 3 splice acceptor position, followed by thymidine with 28.7%, adenine with 6.3%, and guanine with 0.8%. We generated frequency tables and pictograms for the extended donor and acceptor splice consensus regions by analyzing all human exons. Direct Sanger sequencing of all PHEX exons in a sporadic case with HR from the Indian subcontinent revealed an additional novel PHEX mutation (c.1211_1215delACAAAinsTTTACAT, p.Asp404Valfs*5, de novo) located in exon 11.
Mutation analyses revealed two novel mutations and helped to confirm the clinical diagnoses of XLH in two families from India. WES helped to analyze all genes implicated in the underlying disease complex. Mutations at splice positions other than the canonical key sites need further functional investigation to support the assertion of pathogenicity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
APOL1 variants have been associated with renal phenotypes in blacks. To refine clinical outcomes and discover mechanisms of APOL1-associated kidney injury, we analyzed clinical and genomic datasets ...derived from 90 black subjects in the Nephrotic Syndrome Study Network (NEPTUNE), stratified by APOL1 risk genotype. Ninety subjects with proteinuria ≥0.5 g/d were enrolled at first biopsy for primary nephrotic syndrome and followed. Clinical outcomes were determined, and renal histomorphometry and sequencing of Mendelian nephrotic syndrome genes were performed. APOL1 variants were genotyped, and glomerular and tubulointerstitial transcriptomes from protocol renal biopsy cores were analyzed for differential and correlative gene expression. Analyses were performed under the recessive model (high-risk genotype defined by two risk alleles). APOL1 high-risk genotype was significantly associated with a 17 ml/min per 1.73 m(2) lower eGFR and a 69% reduction in the probability of complete remission at any time, independent of histologic diagnosis. Neither APOL1 risk group was enriched for Mendelian mutations. On renal biopsy, high-risk genotype was associated with increased fractional interstitial area, interstitial fibrosis, and tubular atrophy. Risk genotype was not associated with intrarenal APOL1 mRNA expression levels. Differential expression analysis demonstrated an increased steady-state level of five genes associated with the high-risk genotype (CXCL9, CXCL11, and UBD in glomerulus; SNOR14B and MUC13 in tubulointerstitium). APOL1 tubulointerstitial coexpression analysis showed coexpression of APOL1 mRNA levels with a group of intrarenal transcripts that together were associated with increased interstitial fibrosis and tubular atrophy. These data indicate the high-risk APOL1 genotype confers renal risk across histopathologic diagnoses.
PDF
