Characterization of Coding/Noncoding Variants for SHROOM3 in Patients with CKD

Journal of the American Society of Nephrology : JASN
Jeremy W ProkopJozef Lazar

Abstract

Background Interpreting genetic variants is one of the greatest challenges impeding analysis of rapidly increasing volumes of genomic data from patients. For example, SHROOM3 is an associated risk gene for CKD, yet causative mechanism(s) of SHROOM3 allele(s) are unknown.Methods We used our analytic pipeline that integrates genetic, computational, biochemical, CRISPR/Cas9 editing, molecular, and physiologic data to characterize coding and noncoding variants to study the human SHROOM3 risk locus for CKD.Results We identified a novel SHROOM3 transcriptional start site, which results in a shorter isoform lacking the PDZ domain and is regulated by a common noncoding sequence variant associated with CKD (rs17319721, allele frequency: 0.35). This variant disrupted allele binding to the transcription factor TCF7L2 in podocyte cell nuclear extracts and altered transcription levels of SHROOM3 in cultured cells, potentially through the loss of repressive looping between rs17319721 and the novel start site. Although common variant mechanisms are of high utility, sequencing is beginning to identify rare variants involved in disease; therefore, we used our biophysical tools to analyze an average of 112,849 individual human genome sequences f...Continue Reading

References

Feb 16, 2002·Methods : a Companion to Methods in Enzymology·K J Livak, T D Schmittgen
May 29, 2007·PLoS Genetics·Mara E RobuStephen C Ekker
Jul 25, 2008·Journal of the American Society of Nephrology : JASN·Anna KöttgenW H Linda Kao
Nov 1, 2008·Bioinformatics·Andrew D JohnsonPaul I W de Bakker
May 12, 2009·Nature Genetics·Anna KöttgenCaroline S Fox
Oct 24, 2009·The Journal of Biological Chemistry·Hongzhuang PengFrank J Rauscher
Apr 13, 2010·Nature Genetics·John C ChambersJaspal S Kooner
Apr 13, 2010·Nature Genetics·Anna KöttgenCaroline S Fox
Apr 24, 2010·Developmental Cell·Xaralabos VarelasLiliana Attisano
Jun 16, 2010·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Cory BolingerJeffrey D Hildebrand
Aug 12, 2010·PLoS Genetics·Tamra E MeyerUNKNOWN Meta Analysis of Glucose and Insulin Related Traits Consortium
Mar 8, 2011·The Journal of Pathology·Hester HappéDorien J M Peters
May 27, 2011·The Journal of Biological Chemistry·Hideki KatoKatalin Susztak
Oct 8, 2011·PLoS Genetics·Carsten A BögerUNKNOWN CKDGen Consortium
Mar 1, 2012·Nature Methods·Jason Ernst, Manolis Kellis
Apr 12, 2012·Human Molecular Genetics·Jaclyn W EllisUNKNOWN CARe Renal Consortium
May 26, 2012·Science·P Andrew Karplus, Kay Diederichs
Sep 8, 2012·Genome Research·Alan P BoyleMichael Snyder
May 8, 2013·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Sjoerd Johannes Bastiaan Holwerda, Wouter de Laat
Oct 4, 2013·The New England Journal of Medicine·Howard J Jacob
Oct 26, 2013·Nature Protocols·F Ann RanFeng Zhang
Dec 2, 2014·The Journal of Clinical Investigation·Madhav C MenonBarbara Murphy
Feb 20, 2015·Nature·UNKNOWN Roadmap Epigenomics ConsortiumManolis Kellis
Oct 11, 2015·Journal of the American Society of Nephrology : JASN·Jianchun Chen, Raymond C Harris
Mar 5, 2016·Journal of the American Society of Nephrology : JASN·Hadiseh KhaliliDarren Bridgewater
May 20, 2016·American Journal of Physiology. Renal Physiology·Jenny S WongKirk N Campbell
Aug 19, 2016·Nature·Monkol LekUNKNOWN Exome Aggregation Consortium
Aug 24, 2016·Scientific Reports·Eunjeong SeoYong Kyun Kim
Sep 21, 2016·Journal of the American Society of Nephrology : JASN·Helen McNeill, Antoine Reginensi
Feb 17, 2017·Journal of Molecular Modeling·Jeremy W ProkopHoward J Jacob

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Citations

Apr 13, 2018·Journal of the American Society of Nephrology : JASN·Thomas A Drysdale
Feb 7, 2020·SLAS Discovery·Ami KabadiLauren Drowley
Jun 27, 2020·The Journal of Biological Chemistry·Ruchir GuptaJeremy W Prokop
Jun 10, 2020·Clinical Journal of the American Society of Nephrology : CJASN·Jennie Lin, Katalin Susztak
Jun 20, 2019·Frontiers in Genetics·Marisa Cañadas-GarreAlexander Peter Maxwell
Nov 22, 2018·Frontiers in Cardiovascular Medicine·Maria F HughesHelen M Roche
Oct 21, 2018·Journal of the American Society of Nephrology : JASN·Chengguo WeiMadhav C Menon
Dec 31, 2020·Physiological Reports·Chao ZhangFan Fan
Mar 28, 2021·Journal of the American Society of Nephrology : JASN·Jingping YangZhihong Liu
Apr 4, 2021·Genes·Jeremy W ProkopAndré S Bachmann
May 1, 2021·International Journal of Molecular Sciences·Chia-Chun TsengShun-Jen Chang
Sep 3, 2021·JCI Insight·Khadija BanuMadhav C Menon

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