Browsing by Author "Barsh, Gregory S"

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    A Decad(e) of Reasons to Contribute to a PLOS Community-Run Journal
    (PLOS Genetics, 2015-10-05) Copenhaver, Gregory P; Barsh, Gregory S
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    In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress.
    (PLoS Genet, 2015-07) Anderson, Blair R; Howell, David N; Soldano, Karen; Garrett, Melanie E; Katsanis, Nicholas; Telen, Marilyn J; Davis, Erica E; Ashley-Koch, Allison E
    African Americans have a disproportionate risk for developing nephropathy. This disparity has been attributed to coding variants (G1 and G2) in apolipoprotein L1 (APOL1); however, there is little functional evidence supporting the role of this protein in renal function. Here, we combined genetics and in vivo modeling to examine the role of apol1 in glomerular development and pronephric filtration and to test the pathogenic potential of APOL1 G1 and G2. Translational suppression or CRISPR/Cas9 genome editing of apol1 in zebrafish embryos results in podocyte loss and glomerular filtration defects. Complementation of apol1 morphants with wild-type human APOL1 mRNA rescues these defects. However, the APOL1 G1 risk allele does not ameliorate defects caused by apol1 suppression and the pathogenicity is conferred by the cis effect of both individual variants of the G1 risk haplotype (I384M/S342G). In vivo complementation studies of the G2 risk allele also indicate that the variant is deleterious to protein function. Moreover, APOL1 G2, but not G1, expression alone promotes developmental kidney defects, suggesting a possible dominant-negative effect of the altered protein. In sickle cell disease (SCD) patients, we reported previously a genetic interaction between APOL1 and MYH9. Testing this interaction in vivo by co-suppressing both transcripts yielded no additive effects. However, upon genetic or chemical induction of anemia, we observed a significantly exacerbated nephropathy phenotype. Furthermore, concordant with the genetic interaction observed in SCD patients, APOL1 G2 reduces myh9 expression in vivo, suggesting a possible interaction between the altered APOL1 and myh9. Our data indicate a critical role for APOL1 in renal function that is compromised by nephropathy-risk encoding variants. Moreover, our interaction studies indicate that the MYH9 locus is also relevant to the phenotype in a stressed microenvironment and suggest that consideration of the context-dependent functions of both proteins will be required to develop therapeutic paradigms.
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    Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis.
    (PLoS Genet, 2016-10) Castaño-Betancourt, Martha C; Evans, Dan S; Ramos, Yolande FM; Boer, Cindy G; Metrustry, Sarah; Liu, Youfang; den Hollander, Wouter; van Rooij, Jeroen; Kraus, Virginia B; Yau, Michelle S; Mitchell, Braxton D; Muir, Kenneth; Hofman, Albert; Doherty, Michael; Doherty, Sally; Zhang, Weiya; Kraaij, Robert; Rivadeneira, Fernando; Barrett-Connor, Elizabeth; Maciewicz, Rose A; Arden, Nigel; Nelissen, Rob GHH; Kloppenburg, Margreet; Jordan, Joanne M; Nevitt, Michael C; Slagboom, Eline P; Hart, Deborah J; Lafeber, Floris; Styrkarsdottir, Unnur; Zeggini, Eleftheria; Evangelou, Evangelos; Spector, Tim D; Uitterlinden, Andre G; Lane, Nancy E; Meulenbelt, Ingrid; Valdes, Ana M; van Meurs, Joyce BJ
    Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10-8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.