SLC20A1 is involved in urinary tract and urorectal development
Creators: name: Rieke, Johanna Magdalena
name: Zhang, Rong
name: Braun, Doreen
name: Yilmaz, Öznur
name: Japp, Anna S.
name: Lopes, Filipa M.
name: Pleschka, Michael
name: Hilger, Alina C.
name: Schneider, Sophia
name: Newman, William G.
name: Beaman, Glenda M.
name: Nordenskjöld, Agneta
name: Ebert, Anne-Karoline
name: Promm, Martin
name: Rösch, Wolfgang H.
name: Stein, Raimund
name: Hirsch, Karin
name: Schäfer, Frank-Mattias
name: Schmiedeke, Eberhard
name: Boemers, Thomas M.
name: Lacher, Martin
name: Kluth, Dietrich
name: Gosemann, Jan-Hendrik
name: Anderberg, Magnus
name: Barker, Gillian
name: Holmdahl, Gundela
name: Läckgren, Göran
name: Keene, David
name: Cervellione, Raimondo M.
name: Giorgio, Elisa
name: Di Grazia, Massimo
name: Feitz, Wouter F. J.
name: Marcelis, Carlo L. M.
name: Van Rooij, Iris A. L. M.
name: Bökenkamp, Arend
name: Beckers, Goedele M. A.
name: Keegan, Catherine E.
name: Sharma, Amit
name: Dakal, Tikam Chand
name: Wittler, Lars
name: Grote, Phillip
name: Zwink, Nadine
name: Jenetzky, Ekkehart
name: Brusco, Alfredo
name: Thiele, Holger
name: Ludwig, Michael
name: Schweizer, Ulrich
name: Woolf, Adrian S.
name: Odermatt, Benjamin
name: Reutter, Heiko
Publisher: name: Universität Ulm
Year: 2020
Subjects: subject: SLC20A1
subject: urinary tract development
subject: kidney formation
subject: zebrafish development
subject: cloacal malformation
subject: functional genetics
subject: CAKUT
subject: bladder exstrophy-epispadias complex
subject: DDC 610 / Medicine &amp; health
subject: Kidney; Embryology
subject: Kidney; Growth and development
subject: Urinary tract; Growth and development
subject: Zebrafish
subject: Bladder exstrophy
subject: Epispadias
subject: Cloaca; Abnormalities
subject: Niere
subject: Embryonalentwicklung
subject: Zebrabärbling
subject: Blasenekstrophie

description: 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.