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ESPU meeting
S1: BASIC SCIENCE 1
Moderators: Nicolas Kalfa (France), His-Yang Wu (USA)
ESPU Meeting on Wednesday 14, October 2015, 13:30 - 15:00
13:30 - 13:33
S1-1
(PP)
★
KCTD13 GENE-DOSAGE CHANGES ARE ASSOCIATED WITH ANOMALOUS LOWER
URINARY TRACT DEVELOPMENT
Abhishek SETH
1
, Shaye LEWIS
2
, In-Seon CHOI
1
, Chester KOH
1
, Patricio GARGOLLO
1
, David ROTH
1
, Carolina JORGEZ
1
and Dolores LAMB
1
1) Baylor College of Medicine, Scott Department of Urology, Houston, USA - 2) Prairie View A&M University, Prairie View,
USA
PURPOSE
The molecular basis for hypospadias and lower urogenital birth defects is poorly understood. Using comparative genomic
hybridization arrays (aCGH), we have identified a novel candidate gene, potassium channel tetramerization domain
containing 13, KCTD 13 at 16p11.2 in patients with hypospadias, cryptorchidism. KCTD13 encodes a substrate-specific
adapter of a BCR E3 ubiquitin-protein ligase complex, which regulates the cytoskeleton and cell migration. We
hypothesize that gene-dosage defects in KCTD13 result in aberrant development of the GU tract.
MATERIAL AND METHODS
Genomic DNA from patients with hypospadias, cryptorchidism, ambiguous genitalia and control patients was analyzed by
aCGH. Quantitative PCR was performed using CNV-taqman assays to validate putative regions of deletion or duplication.
In-situ hybridization (ISH) of mouse embryos was performed to elucidate KCTD13 expression. Phenotypic analyses of
Kctd13 +/- and -/- mice are being performed.
RESULTS
A de novo 16p11.2 deletion encompassing KCTD13 was identified in a child with hypospadias by aCGH. A ~600 kb
paternally (asymptomatic) inherited duplication in the same region was identified in a second patient with hypospadias,
cryptorchidism and micropenis. We identified 2 more patients in our cohort and 31 other patients in literature and public
databases (DECIPHER) with defects in KCTD13 and concomitant GU anomalies. These GU anomalies range from ectopic
testes to ambiguous genitalia. In-situ hybridization of mouse embryos shows robust expression of KCTD13 in the entire
urinary tract, particularly in the genital tubercle. Immunofluorescent staining of mouse urethra shows robust expression
of KCTD13 in the urothelium. Preliminary phenotypic analyses of Kctd13 +/- mice reveals cryptorchidism in 2/4 (50%)
of mice and 0/4 control mice.
CONCLUSIONS
KCTD13 gene-dosage changes are found in a subset of children with hypospadias, cryptorchidism and lower GU tract
anomalies. Using CRISPR genome editing, a kctd13 +/- and null mouse was produced and currently undergoing
phenotypic analyses to prove causation beyond association.