SLC20A1 Is Involved in Urinary Tract and Urorectal Development

Rieke JM, Zhang R, Braun D, Yilmaz Ö, Japp AS, Lopes FM, Pleschka M, Hilger AC, Schneider S, Newman WG, Beaman GM, Nordenskjöld A, Ebert AK, Promm M, Rösch WH, Stein R, Hirsch K, Schäfer FM, Schmiedeke E, Boemers TM, Lacher M, Kluth D, Gosemann JH, Anderberg M, Barker G, Holmdahl G, Läckgren G, Keene D, Cervellione RM, Giorgio E, Di Grazia M, Feitz WF, Marcelis CL, Van Rooij IA, Bökenkamp A, Beckers GM, Keegan CE, Sharma A, Dakal TC, Wittler L, Grote P, Zwink N, Jenetzky E, Brusco A, Thiele H, Ludwig M, Schweizer U, Woolf AS, Odermatt B, Reutter HM (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Book Volume: 8

Article Number: 567

DOI: 10.3389/fcell.2020.00567

Abstract

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.

Authors with CRIS profile

Involved external institutions

Manchester University NHS Foundation Trust (MFT) United Kingdom (GB) Uppsala University Sweden (SE) Universitätsklinikum Bonn Germany (DE) Universitätsklinikum Ulm Germany (DE) University of Michigan United States (USA) (US) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) Netherlands (NL) Max-Planck-Institut für molekulare Genetik / Max Planck Institute for Molecular Genetics Germany (DE) Universitätsklinikum Regensburg Germany (DE) Universität Leipzig Germany (DE) Universitätsmedizin der Johannes Gutenberg-Universität Mainz Germany (DE) Universitätsklinikum Mannheim / University Medical Centre Mannheim (Universitätsmedizin Mannheim) Germany (DE) Goethe-Universität Frankfurt am Main Germany (DE) University of Turin / Università degli Studi di Torino (UNITO) Italy (IT) Mohanlal Sukhadia University / University of Udaipur India (IN) Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra Netherlands (NL) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Queen Silvia Children’s Hospital Sweden (SE) Karolinska Institute Sweden (SE) Royal Manchester Children's Hospital United Kingdom (GB) Klinikverbund Bremen (Gesundheit Nord) Germany (DE) Uppsala University Hospital / Akademiska sjukhuset Sweden (SE) Fondazione IRCCS: Istituto Nazionale dei Tumori Italy (IT) Skåne University Hospital / Skånes universitetssjukhus Sweden (SE) Kinderkrankenhaus Amsterdamer Straße Germany (DE) Universität zu Köln Germany (DE)

How to cite

APA:

Rieke, J.M., Zhang, R., Braun, D., Yilmaz, Ö., Japp, A.S., Lopes, F.M.,... Reutter, H.M. (2020). SLC20A1 Is Involved in Urinary Tract and Urorectal Development. Frontiers in Cell and Developmental Biology, 8. https://doi.org/10.3389/fcell.2020.00567

MLA:

Rieke, Johanna Magdalena, et al. "SLC20A1 Is Involved in Urinary Tract and Urorectal Development." Frontiers in Cell and Developmental Biology 8 (2020).

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