A Uromodulin Mutation Drives Autoimmunity and Kidney Mononuclear Phagocyte Endoplasmic Reticulum Stress

Plotkin, Matthew; O’Brien, Charles A.; Goellner, Joseph J.; Williams, Joshua; Carter, Weleetka; Sharma, Smriti; Stone, Annjanette

doi:10.1016/j.ajpath.2020.08.015

Cited by 7 publications

(7 citation statements)

References 41 publications

(40 reference statements)

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“…GRCh38, Genome Reference Consortium Human Build 38; rs, Reference SNP; HGVS, Human Genome Variation Society; AA, amino acid; ClinVar, Clinical Variations database; VEP, Variant Effect Predictor; neu, neutral; nonpol, non polar; pol, polar; neg, negative; pos, positive; ALFA, National Center for Biotechnology Information (NCBI) Allele Frequency Aggregator ( https://www.ncbi.nlm.nih.gov/snp/docs/gsr/alfa/ ); B, benign; LB, likely benign; LP, likely pathogenic; TOPMed, Trans-Omics for Precision Medicine Program ( 50 ). * Using CRISPR-Cas9 gene editing, a mouse model with the homologous mutation was created that showed intracellular and secreted UMOD aggregates, but characterization of ER stress or kidney function was not shown ( 52 ). In vitro trafficking of this UMOD isoform was similar to the wild type (in vitro score of one) ( 20 ).…”

Section: Resultsmentioning

confidence: 99%

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An intermediate-effect size variant in UMOD confers risk for chronic kidney disease

Olinger

Schaeffer

Kidd

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD), while common low-impact variants strongly associate with kidney function and the risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large-population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations, patient samples, and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in the Genome Aggregation Database (gnomAD), with minor allele frequency (MAF) ranging from 10 −5 to 10 −3 . Among them, the missense variant p.Thr62Pro is detected in ∼1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD, and is associated with kidney failure in the 100,000 Genomes Project (odds ratio [OR] = 3.99 [1.84 to 8.98]) and the UK Biobank (OR = 4.12 [1.32 to 12.85). Compared with canonical ADTKD mutations, the p.Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD and an intermediate reduction of urinary uromodulin levels, in line with an intermediate trafficking defect in vitro and modest induction of endoplasmic reticulum (ER) stress. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD -associated kidney diseases and provides insights into the mechanisms of ADTKD and the genetic architecture of CKD.

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Section: Resultsmentioning

confidence: 99%

“… * Using CRISPR-Cas9 gene editing, a mouse model with the homologous mutation was created that showed intracellular and secreted UMOD aggregates, but characterization of ER stress or kidney function was not shown ( 52 ). In vitro trafficking of this UMOD isoform was similar to the wild type (in vitro score of one) ( 20 ).…”

Section: Resultsmentioning

confidence: 99%

An intermediate-effect size variant in UMOD confers risk for chronic kidney disease

Olinger

Schaeffer

Kidd

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Real-time QPCR was performed as described by Plotkin et al [ 41 ]. Total RNA was isolated from PBMCs of 10 breast cancer patients, including 5 patients with normal LVEF and 5 patients with abnormal LVEF before, and after the first cycle of DOX-based chemotherapy using RNeasy mini kit (Qiagen, Valencia, CA, USA), following manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

Genome-Wide DNA Methylation Signatures Predict the Early Asymptomatic Doxorubicin-Induced Cardiotoxicity in Breast Cancer

Bauer

Тодорова

Stone

et al. 2021

Cancers

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Chemotherapy with doxorubicin (DOX) may cause unpredictable cardiotoxicity. This study aimed to determine whether the methylation signature of peripheral blood mononuclear cells (PBMCs) prior to and after the first cycle of DOX-based chemotherapy could predict the risk of cardiotoxicity in breast cancer patients. Cardiotoxicity was defined as a decrease in left ventricular ejection fraction (LVEF) by >10%. DNA methylation of PBMCs from 9 patients with abnormal LVEF and 10 patients with normal LVEF were examined using Infinium HumanMethylation450 BeadChip. We have identified 14,883 differentially methylated CpGs at baseline and 18,718 CpGs after the first cycle of chemotherapy, which significantly correlated with LVEF status. Significant differentially methylated regions (DMRs) were found in the promoter and the gene body of SLFN12, IRF6 and RNF39 in patients with abnormal LVEF. The pathway analysis found enrichment for regulation of transcription, mRNA splicing, pathways in cancer and ErbB2/4 signaling. The preliminary results from this study showed that the DNA methylation profile of PBMCs may predict the risk of DOX-induced cardiotoxicity prior to chemotherapy. Further studies with larger cohorts of patients are needed to confirm these findings.

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“…REVEL, rare exome variant ensemble learner (19) (a score >0.5 corresponds to a sensitivity of 0.75 and specificity of 0.89 for pathogenic variants in the training dataset), ClinVar last accessed 04.2021, B, benign; LB, likely benign; P, pathogenic; LP, likely pathogenic; VUS, variant of unknown significance. # Using CRISPR-Cas9 gene editing, a mouse model with the homologous mutation was created that showed intracellular and secreted UMOD aggregates but characterization of ER stress or kidney function was not shown (47). In vitro trafficking of this UMOD isoform was similar to wild type (in vitro score 1) (20) ¶ In the reported ADTKD family, the index patient displayed kidney failure at 20-24 years and intracellular UMOD accumulation was described in the kidney biopsy.…”

Section: Data Availabilitymentioning

confidence: 99%

An intermediate effect size variant in UMOD confers risk for chronic kidney disease

Olinger

Schaeffer

Kidd

et al. 2021

Preprint

View full text Add to dashboard Cite

The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare, large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD) while common, low-effect variants strongly associate with kidney function and risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in gnomAD with MAF ranging from 10-5 to 10-3. Among them, the missense variant p.Thr62Pro is detected in ~1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD and is associated with kidney failure in the 100,000 Genomes Project (OR 3.99; 1.84-8.98) and the UK Biobank (OR 4.12; 1.32-12.85). Compared to canonical ADTKD mutations, the p.Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD, intermediate reduction of urinary UMOD levels, in line with an intermediate trafficking defect in vitro. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD-associated kidney diseases and provides novel insights into the mechanisms of ADTKD and the genetic architecture of CKD.

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A Uromodulin Mutation Drives Autoimmunity and Kidney Mononuclear Phagocyte Endoplasmic Reticulum Stress

Cited by 7 publications

References 41 publications

An intermediate-effect size variant in UMOD confers risk for chronic kidney disease

An intermediate-effect size variant in UMOD confers risk for chronic kidney disease

Genome-Wide DNA Methylation Signatures Predict the Early Asymptomatic Doxorubicin-Induced Cardiotoxicity in Breast Cancer

An intermediate effect size variant in UMOD confers risk for chronic kidney disease

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