In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress.
Abstract
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.
Type
Journal articleSubject
AnimalsApolipoproteins
Clustered Regularly Interspaced Short Palindromic Repeats
Flow Cytometry
Gene Knockdown Techniques
Genetic Predisposition to Disease
Genetic Variation
Glomerular Filtration Rate
Glomerulonephritis, Membranous
Humans
Kidney Glomerulus
Lipoproteins, HDL
Microscopy, Electron, Transmission
Molecular Motor Proteins
Morpholinos
Myosin Heavy Chains
Zebrafish
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https://hdl.handle.net/10161/10832Published Version (Please cite this version)
10.1371/journal.pgen.1005349Publication Info
Anderson, Blair R; Howell, David N; Soldano, Karen; Garrett, Melanie E; Katsanis,
Nicholas; Telen, Marilyn J; ... Ashley-Koch, Allison E (2015). In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects
and Epistasis under Anemic Stress. PLoS Genet, 11(7). pp. e1005349. 10.1371/journal.pgen.1005349. Retrieved from https://hdl.handle.net/10161/10832.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Allison Elizabeth Ashley-Koch
Professor in Medicine
One of my major research foci is in the genetic basis of psychiatric and neurological
disorders. I am currently involved in studies to dissect the genetic etiology of
attention deficit hyperactivity disorder (ADHD), autism, chiari type I malformations,
essential tremor, and neural tube defects. Additional research foci include genetic
modifiers of sickle cell disease, and genetic contributions to birth outcomes, particularly
among African American women.
Erica Ellen Davis
Associate Professor of Pediatrics
Two key questions thematically underscore my research in the Center for Human Disease
Modeling at Duke University: First of all, how can variation at the DNA level be functionally
interpreted beyond the resolution of genetics arguments alone? Secondly, once empowered
with functional information about genetic variants, how can pathogenic alleles be
mapped back to disease phenotypes? Using the ciliary disease module as a model system
of investigation, we are using multidisciplinary tactics to addr
David Noble Howell
Professor of Pathology
A major focus of both my clinical practice and investigative work is the diagnosis
and treatment of disorders affecting solid-organ transplant recipients, particularly
infectious complications. For the past 15 years, I have served as the primary pathologist
for one of the largest lung transplant programs in the world; in the process contributing
to over 20 peer-reviewed publications on complications of lung transplantation, including
infections, gastroesophageal reflux, tumors, and antibod
Nicholas Katsanis
Jean and George W. Brumley, Jr., M.D. Professor of Developmental Biology
Marilyn Jo Telen
Wellcome Clinical Distinguished Professor of Medicine in Honor of R. Wayne Rundles,
M.D.
Dr. Telen is recognized as an expert in the biochemistry and molecular genetics of
blood group antigens and the pathophysiological mechanisms of vaso-occlusion in sickle
cell disease. She is the Director of the Duke Comprehensive Sickle Cell Center.
Dr. Telen's laboratory focuses on structure/function analysis of membrane proteins
expressed by erythroid cells, as well as the role of these proteins in non-erythroid
cells. Proteins are also studied in transfectant systems, and re
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