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15:56 - 15:59
S2-8
(PP)
KCNG4: A NOVEL GENE CANDIDATE UNDERLYING VESICOURETERAL REFLUX
Abhishek SETH, In-Seon CHOI, Chester KOH, Patricio GARGOLLO, David ROTH, Carolina JORGEZ and Dolores LAMB
Baylor College of Medicine, Scott Department of Urology, Houston, USA
PURPOSE
A genetic basis for VUR has been inferred through linkage analysis studies, yet few candidate genes are known. Using
comparative genomic hybridization microarray analysis (aCGH), we identified KCNG4 as a novel candidate gene
underlying vesicoureteral reflux. KCNG4 encodes a protein that functions as a modulatory unit in a voltage gated
potassium channel. We hypothesize that gene dosage changes in the KCNG4 gene are responsible for VUR in a subset of
children.
MATERIAL AND METHODS
Genomic DNA from 35 pediatric patients with VUR and 5 control patients was analyzed by aCGH using 720K NimbleGen
arrays (Roche). Quantitative PCR was performed using CNV-taqman assays to validate putative regions of duplication
or deletion that were distinct from CNVs found throughout the genome.
RESULTS
We identified a microdeletion of 74,043 base pairs spanning a single gene - KCNG4 (16q24.1). This deletion in KCNG4
was validated using qPCR. This deletion was outside areas of known benign copy number variations (CNVs) and was not
present in healthy, disease-free controls. Incidence of known defects in KCNG4 in the population of individuals tested
for a variety of indications is 0.04%, as extracted from the DECIPHER database. We identified two patients in the
DECIPHER database with duplications in KCNG4 and concomitant GU tract anomalies including VUR and
hypospadias. We conducted in-situ hybridization and found robust KCNG4 expression in the developing GU tract of
mouse embryos. Initial phenotypic analysis of the first Kcng4 -/- mouse showed bilateral VUR.
CONCLUSIONS
We used aCGH analysis to identify KCNG4 as a possible novel gene defect that may be responsible for VUR in a subset
of patients. Recapitulation of VUR in KCNG4 knockout mouse models would prove causation beyond association. Using
CRISPR genome editing, we have produced Kcng4 knockout mice and are in the process of conducting phenotypic
analyses.