Collagen IV Gene Mutations in Adults With Bilateral Renal Cysts and CKD.
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ABSTRACT:
SUBMITTER: Gulati A
PROVIDER: S-EPMC6943786 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
Publications
Collagen IV Gene Mutations in Adults With Bilateral Renal Cysts and CKD.
Gulati Ashima A Sevillano Angel M AM Praga Manuel M Gutierrez Eduardo E Alba Ignacio I Dahl Neera K NK Besse Whitney W Choi Jungmin J Somlo Stefan S
Kidney international reports 20190911 1
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Project description:Type IV collagen is a major component of basement membranes. We have characterized 11 mutations in emb-9, the alpha1(IV) collagen gene of Caenorhabditis elegans, that result in a spectrum of phenotypes. Five are substitutions of glycines in the Gly-X-Y domain and cause semidominant, temperature-sensitive lethality at the twofold stage of embryogenesis. One is a glycine substitution that causes recessive, non-temperature-sensitive larval lethality. Three putative null alleles, two nonsense mutations and a deletion, all cause recessive, non-temperature-sensitive lethality at the threefold stage of embryogenesis. The less severe null phenotype indicates that glycine substitution containing mutant chains dominantly interfere with the function of other molecules. The emb-9 null mutants do not stain with anti-EMB-9 antisera and show intracellular accumulation of the alpha2(IV) chain, LET-2, indicating that LET-2 assembly and/or secretion requires EMB-9. Glycine substitutions in either EMB-9 or LET-2 cause intracellular accumulation of both chains. The degree of intracellular accumulation differs depending on the allele and temperature and correlates with the severity of the phenotype. Temperature sensitivity appears to result from reduced assembly/secretion of type IV collagen, not defective function in the basement membrane. Because the dominant interference of glycine substitution mutations is maximal when type IV collagen secretion is totally blocked, this interference appears to occur intracellularly, rather than in the basement membrane. We suggest that the nature of dominant interference caused by mutations in type IV collagen is different than that caused by mutations in fibrillar collagens.
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Project description: Not available
| S-EPMC7335950 | biostudies-literature
Project description:Rationale & objectivePathogenic variants in type IV collagen have been reported to account for a significant proportion of chronic kidney disease. Accordingly, genetic testing is increasingly used to diagnose kidney diseases, but testing also may reveal rare missense variants that are of uncertain clinical significance. To aid in interpretation, computational prediction (called in silico) programs may be used to predict whether a variant is clinically important. We evaluate the performance of in silico programs for COL4A3/A4/A5 variants.Study design setting & participantsRare missense variants in COL4A3/A4/A5 were identified in disease cohorts, including a local focal segmental glomerulosclerosis (FSGS) cohort and publicly available disease databases, in which they are categorized as pathogenic or benign based on clinical criteria.Tests compared & outcomesAll rare missense variants identified in the 4 disease cohorts were subjected to in silico predictions using 12 different programs. Comparisons between the predictions were compared with: (1) variant classification (pathogenic or benign) in the cohorts and (2) functional characterization in a randomly selected smaller number (17) of pathogenic or uncertain significance variants obtained from the local FSGS cohort.ResultsIn silico predictions correctly classified 75% to 97% of pathogenic and 57% to 100% of benign COL4A3/A4/A5 variants in public disease databases. The congruency of in silico predictions was similar for variants categorized as pathogenic and benign, with the exception of benign COL4A5 variants, in which disease effects were overestimated. By contrast, in silico predictions and functional characterization classified all 9 pathogenic COL4A3/A4/A5 variants correctly that were obtained from a local FSGS cohort. However, these programs also overestimated the effects of genomic variants of uncertain significance when compared with functional characterization. Each of the 12 in silico programs used yielded similar results.LimitationsOverestimation of in silico program sensitivity given that they may have been used in the categorization of variants labeled as pathogenic in disease repositories.ConclusionsOur results suggest that in silico predictions are sensitive but not specific to assign COL4A3/A4/A5 variant pathogenicity, with misclassification of benign variants and variants of uncertain significance. Thus, we do not recommend in silico programs but instead recommend pursuing more objective levels of evidence suggested by medical genetics guidelines.
| S-EPMC8039416 | biostudies-literature
Project description:Background and aimsMetabolic syndrome is common nowadays and may increase risk of hypertension, type 2 diabetes mellitus, cardiovascular complications and even mortality. Renal cysts are also frequently found during routine examination. However, the relationship between simple renal cysts (SRCs) and metabolic syndrome remains unclear. This study aimed to investigate the association of SRCs with metabolic syndrome.MethodsA total of 16,216 subjects aged ≥18 years were enrolled in this study. SRCs were diagnosed with ultrasonography by finding: sharp, thin posterior walls, a round/oval shape, absence of internal echoes, and posterior enhancement. SRCs were categorized by number (0, 1, and ≥2) and size (<2 and ≥2 cm). Metabolic syndrome was diagnosed according to the consensus statement from the International Diabetes Federation.ResultsIn multivariate analysis, SRCs were positively related to metabolic syndrome (OR: 1.18, 95% CI: 1.06-1.34). The risk of metabolic syndrome was higher for SRCs with a number ≥2 (OR: 1.35, 95% CI: 1.08-1.68) and size ≥2 cm (OR: 1.33, 95% CI: 1.10-1.61). When considering the SRC number and size concomitantly, SRCs with a number ≥2/size ≥2 cm (OR: 1.42, 95% CI: 1.02-1.98) or <2/size ≥2 cm (OR: 1.30, 95% CI: 1.04-1.62) were positively related to metabolic syndrome.ConclusionsSimple renal cysts were found to be related to a higher risk of metabolic syndrome, and the association is more significant in those with larger (sizes ≥2cm) or plural (numbers ≥2) SRCs.
| S-EPMC9669605 | biostudies-literature
Project description:Background and objectivesPremenopausal women who undergo bilateral oophorectomy are at a higher risk of morbidity and mortality. Given the potential benefits of estrogen on kidney function, we hypothesized that women who undergo bilateral oophorectomy are at higher risk of CKD.Design, setting, participants, & measurementsWe performed a population-based cohort study of 1653 women residing in Olmsted County, Minnesota who underwent bilateral oophorectomy before age 50 years old and before the onset of menopause from 1988 to 2007. These women were matched by age (±1 year) to 1653 referent women who did not undergo oophorectomy. Women were followed over a median of 14 years to assess the incidence of CKD. CKD was primarily defined using eGFR (eGFR<60 ml/min per 1.73 m2 on two occasions >90 days apart). Hazard ratios were derived using Cox proportional hazards models, and absolute risk increases were derived using Kaplan-Meier curves at 20 years. All analyses were adjusted for 17 chronic conditions present at index date, race, education, body mass index, smoking, age, and calendar year.ResultsWomen who underwent bilateral oophorectomy had a higher risk of eGFR-based CKD (211 events for oophorectomy and 131 for referent women; adjusted hazard ratio, 1.42; 95% confidence interval, 1.14 to 1.77; absolute risk increase, 6.6%). The risk was higher in women who underwent oophorectomy at age ≤45 years old (110 events for oophorectomy and 60 for referent women; adjusted hazard ratio, 1.59; 95% confidence interval, 1.15 to 2.19; absolute risk increase, 7.5%).ConclusionsPremenopausal women who undergo bilateral oophorectomy, particularly those ≤45 years old, are at higher risk of developing CKD, even after adjusting for multiple chronic conditions and other possible confounders present at index date.PodcastThis article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_10_11_CJASNPodcast_18_1.
| S-EPMC6237067 | biostudies-literature
Project description:Collagen IV is an essential structural protein in all metazoans. It provides a scaffold for the assembly of basement membranes, a specialized form of extracellular matrix, which anchors and signals cells and provides microscale tensile strength. Defective scaffolds cause basement membrane destabilization and tissue dysfunction. Scaffolds are composed of α-chains that coassemble into triple-helical protomers of distinct chain compositions, which in turn oligomerize into supramolecular scaffolds. Chloride ions mediate the oligomerization via NC1 trimeric domains, forming an NC1 hexamer at the protomer-protomer interface. The chloride concentration-"chloride pressure"-on the outside of cells is a primordial innovation that drives the assembly and dynamic stabilization of collagen IV scaffolds. However, a Cl-independent mechanism is operative in Ctenophora, Ecdysozoa, and Rotifera, which suggests evolutionary adaptations to environmental or tissue conditions. An understanding of these exceptions, such as the example of Drosophila, could shed light on the fundamentals of how NC1 trimers direct the oligomerization of protomers into scaffolds. Here, we investigated the NC1 assembly of Drosophila. We solved the crystal structure of the NC1 hexamer, determined the chain composition of protomers, and found that Drosophila adapted an evolutionarily unique mechanism of scaffold assembly that requires divalent cations. By studying the Drosophila case we highlighted the mechanistic role of chloride pressure for maintaining functionality of the NC1 domain in humans. Moreover, we discovered that the NC1 trimers encode information for homing protomers to distant tissue locations, providing clues for the development of protein replacement therapy for collagen IV genetic diseases.
| S-EPMC10694668 | biostudies-literature
Project description:Renal infarction (RI) is frequently misdiagnosed or diagnosed late because of its rarity and nonspecific clinical presentation, which may result in irreversible damage to the renal parenchyma or increase the risk of other embolic events affecting additional organs. Multiple causal mechanisms and cases of idiopathic RI have been reported, but the causal factors are not clear in most cases.Here, we report the case of a patient with heterochronic bilateral RI caused by thrombophilia. Although he had several risk factors for hypercoagulation disorders, two gene mutations-MTHFR 677 C>T and PLG 1858G>A-were identified by genome sequencing of the entire exome. The findings suggest the possibility of a synergistic relationship between the two gene mutations.Thus, screening for gene mutations may provide additional clues for clarifying the cause of RI and thrombophilia.
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Project description:BackgroundEstimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) study or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations may not be accurate for Asians; thus, we developed modified eGFR equations for Taiwanese adults.MethodsThis cross-sectional study compared the Taiwanese eGFR equations, the MDRD study, and the CKD-EPI equations with inulin clearance (Cin). A total of 695 adults including 259 healthy volunteers and 436 CKD patients were recruited. Participants from the Kaohsiung Medical University Hospital were used as the development set (N = 556) to develop the Taiwanese eGFR equations, whereas participants from the National Taiwan University Hospital were used as the validation set (N = 139) for external validation.ResultsThe Taiwanese eGFR equations were developed by using the extended Bland-Altman plot in the development set. The Taiwanese MDRD equation was 1.309 × MDRD0.912, Taiwanese CKD-EPI was 1.262×CKD-EPI0.914 and Taiwanese four-level CKD-EPI was 1.205 × four-level CKD-EPI0.914. In the validation set, the Taiwanese equations had the lowest bias, the Taiwanese equations and the Japanese CKD-EPI equation had the lowest RMSE, whereas the Taiwanese and the Japanese equations had the best precision and the highest P30 among all equations. However, the Taiwanese MDRD equation had higher concordance correlation than did the Taiwanese CKD-EPI, the Taiwanese four-level CKD-EPI and the Japanese equations. Moreover, only the Taiwanese equations had no proportional bias among all of the equations. Finally, the Taiwanese MDRD equation had the best diagnostic performance in terms of ordinal logistic regression among all of the equations.ConclusionThe Taiwanese MDRD equation is better than the MDRD, CKD-EPI, Japanese, Asian, Thai, Taiwanese CKD-EPI, and Taiwanese four-level CKD-EPI equations for Taiwanese adults.
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Project description:Renal cysts are a common imaging finding. Although most cysts never have symptoms, some cause pain, collecting system compression, hematuria, hypertension, and secondary infection. The mere presence of a cyst is not an indication for intervention, but treatment may be indicated in symptomatic patients or those with secondary obstruction. Urinomas generally are a contained collection of urine outside of the normal pathways where urine travels. As such, urinomas can arise anywhere from the upper abdomen down into the low pelvis and have a variety of etiologies. Ureteral obstruction with forniceal rupture and trauma (blunt, penetrating, or iatrogenic) are the most common causes of urinomas. When urinomas arise spontaneously, the likely cause varies with the patient's age. Blunt or penetrating trauma can cause perinephric urinomas by two mechanisms-direct disruption of the pelvis or collecting system or by degeneration of nonviable tissue. These urinomas are often perinephric, but can also occur in a subcapsular location. This review will discuss diagnosis, classification, and treatment of renal cysts and urinomas.
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Project description:Renal hypodysplasia (RHD) is a heterogeneous condition encompassing a spectrum of kidney development defects including renal agenesis, hypoplasia, and (cystic) dysplasia. Heterozygous mutations of several genes have been identified as genetic causes of RHD with various severity. However, these genes and mutations are not associated with bilateral renal agenesis, except for RET mutations, which could be involved in a few cases. The pathophysiological mechanisms leading to total absence of kidney development thus remain largely elusive. By using a whole-exome sequencing approach in families with several fetuses with bilateral renal agenesis, we identified recessive mutations in the integrin α8-encoding gene ITGA8 in two families. Itga8 homozygous knockout in mice is known to result in absence of kidney development. We provide evidence of a damaging effect of the human ITGA8 mutations. These results demonstrate that mutations of ITGA8 are a genetic cause of bilateral renal agenesis and that, at least in some cases, bilateral renal agenesis is an autosomal-recessive disease.
| S-EPMC3928807 | biostudies-literature