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An intermediate-effect size variant in UMOD confers risk for chronic kidney disease
E. Olinger, C. Schaeffer, K. Kidd, EAE. Elhassan, Y. Cheng, I. Dufour, G. Schiano, H. Mabillard, E. Pasqualetto, P. Hofmann, DG. Fuster, AD. Kistler, IJ. Wilson, S. Kmoch, L. Raymond, T. Robert, Genomics England Research Consortium, KU. Eckardt,...
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
NLK
Free Medical Journals
od 1915 do Před 6 měsíci
Freely Accessible Science Journals
od 1915 do Před 6 měsíci
PubMed Central
od 1915 do Před 6 měsíci
Europe PubMed Central
od 1915 do Před 6 měsíci
Open Access Digital Library
od 1915-01-15
Open Access Digital Library
od 1915-01-01
PubMed
35947615
DOI
10.1073/pnas.2114734119
Knihovny.cz E-zdroje
- MeSH
- chronická renální insuficience * genetika MeSH
- heterozygot MeSH
- lidé MeSH
- mutace MeSH
- uromodulin * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
Biosciences Institute Newcastle University Newcastle upon Tyne NE1 3BZ United Kingdom
Centre for Integrative Biological Signalling Studies University of Freiburg D 79106 Freiburg Germany
Department of Medicine Cantonal Hospital Frauenfeld 8501 Frauenfeld Switzerland
Department of Medicine Royal College of Surgeons in Ireland 1297 Dublin Ireland
Division of Nephrology Beaumont General Hospital 1297 Dublin Ireland
Division of Nephrology Cliniques Universitaires Saint Luc 1200 Brussels Belgium
Faculty of Biology University of Freiburg D 79106 Freiburg Germany
Genetics Department Laboratoire Eurofins Biomnis Lyon 69007 France
Institute of Physiology University of Zurich CH 8057 Zurich Switzerland
Section on Nephrology Wake Forest School of Medicine Winston Salem NC 27101
Citace poskytuje Crossref.org
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