TY  - JOUR
A1  - Rieke, Johanna Magdalena
A1  - Zhang, Rong
A1  - Braun, Doreen
A1  - Yilmaz, Öznur
A1  - Japp, Anna S.
A1  - Lopes, Filipa M.
A1  - Pleschka, Michael
A1  - Hilger, Alina Christine
A1  - Schneider, Sophia
A1  - Newman, William G.
A1  - Schneider, Sophia
A1  - Newman, William G.
A1  - Beaman, Glenda M.
A1  - Nordenskjöld, Agneta
A1  - Ebert, Anne-Karoline
A1  - Promm, Martin
A1  - Rösch, Wolfgang H.
A1  - Stein, Raimund
A1  - Hirsch, Karin
A1  - Schäfer, Frank-Mattias
A1  - Schmiedeke, Eberhard
A1  - Boemers, Thomas M.
A1  - Lacher, Martin
A1  - Kluth, Dietrich
A1  - Gosemann, Jan-Hendrik
A1  - Anderberg, Magnus
A1  - Barker, Gillian
A1  - Holmdahl, Gundela
A1  - Läckgren, Göran
A1  - Keene, David
A1  - Cervellione, Raimondo M.
A1  - Giorgio, Elisa
A1  - Di Grazia, Massimo
A1  - Feitz, Wouter F. J.
A1  - Marcelis, Carlo L. M.
A1  - Rooij, Iris Antonia Leonarda Martina van
A1  - Bökenkamp, Arend
A1  - Beckers, Goedele M. A.
A1  - Keegan, Catherine E.
A1  - Sharma, Amit
A1  - Dakal, Tikam Chand
A1  - Wittler, Lars
A1  - Grote, Phillip
A1  - Zwink, Nadine
A1  - Jenetzky, Ekkehart
A1  - Brusco, Alfredo
A1  - Thiele, Holger
A1  - Ludwig, Michael
A1  - Schweizer, Ulrich
A1  - Woolf, Adrian S.
A1  - Odermatt, Benjamin
A1  - Reutter, Heiko
T1  - SLC20A1 is involved in urinary tract and urorectal development
T2  - Frontiers in cell and developmental biology
N2  - Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC.
KW  - SLC20A1
KW  - urinary tract development
KW  - kidney formation
KW  - zebrafish development
KW  - cloacal malformation
KW  - functional genetics
KW  - CAKUT
KW  - bladder exstrophy-epispadias complex
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/55396
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-553961
SN  - 2296-634X
VL  - 8
IS  - 567
PB  - Frontiers Media
CY  - Lausanne
ER  -