SLC20A1 Is Involved in Urinary Tract and Urorectal Development

Rieke, Johanna Magdalena; Zhang, Rong; Braun, Doreen; Yılmaz, Öznur; Japp, Anna Sophia; Lopes, Filipa; Pleschka, Michael; Hilger, Alina C.; Schneider, Sophia; Newman, William G.; Nordenskjöld, Agneta; Ebert, A.; Promm, Martin; Rösch, Wolfgang; Stein, Raimund; Hirsch, Karin; Schäfer, Frank Mattias; Schmiedeke, Eberhard; Boemers, Thomas M.; Lacher, Martin; Kluth, Dietrich; Gosemann, Jan Hendrik; Anderberg, Magnus; Barker, Gillian; Holmdahl, Gundela; Läckgren, Göran; Keene, David; Cervellione, Raimondo M.; Giorgio, Elisa; Grazia, Massimo Di; Feitz, W. F. J.; Marcelis, Carlo; Rooij, Iris A. L. M. van; Bökenkamp, Arend; Beckers, Goedele M.A.; Keegan, Catherine E.; Sharma, Amit; Dakal, Tikam Chand; Wittler, Lars; Grote, Phillip; Zwink, Nadine; Jenetzky, Ekkehart; Brusco, Alfredo; Thiele, Holger; Ludwig, Michael; Schweizer, Ulrich; Woolf, Adrian S.; Odermatt, Benjamin; Reutter, Heiko

doi:10.3389/fcell.2020.00567

Cited by 25 publications

(21 citation statements)

References 26 publications

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“…Recently, Rieke et al described SLC20A1 , encoding a sodium-phosphate symporter, as the first putative monogenic dominant disease gene for nonsyndromic BEEC. 29 They identified monoallelic dominant de novo variants in affected individuals in three independent families and were able to support their human genetic data by immunohistochemistry staining of SLC20A1 in non-BEEC human embryos in the urogenital sinus and morpholino knockdown and rescue experiments in the zebrafish ortholog slc20a1a . 29 While the evidence provided by Rieke et al to support SLC20A1 as the first monogenic disease gene for the BEEC is strong, these findings warrant replication in further cohorts and should currently be taken with caution in the setting of routine genetic prenatal testing.…”

Section: Putative Nonsyndromic Disease Gene Slc20a1mentioning

confidence: 86%

Genetic Counseling for Bladder Exstrophy-Epispadias Complex

Reutter

Holmdahl

2021

Eur J Pediatr Surg

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Bladder exstrophy-epispadias complex (BEEC) represents the severe end of the uro-rectal malformation spectrum and has profound impact on continence, sexual, and renal function. Treatment of BEEC is primarily surgical, and the main goals are safe closure of the abdominal wall, urinary continence while preserving renal function, and adequate cosmetic and functional genital reconstruction. Psychosocial and psychosexual outcomes and adequate health-related quality of life depend on long-term multidisciplinary care. The overall outcome is now considered very positive and affected individuals usually lead self-determined and independent lives with the desire to start their own families later in life. Certainty about the risk of recurrence and the provision of information about the current state of knowledge about the identified genetic causes with high penetrance will have an impact on family planning for healthy parents with an affected child and for affected individuals themselves. This review addresses this information and presents the current state of knowledge.

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Section: Putative Nonsyndromic Disease Gene Slc20a1mentioning

confidence: 86%

Genetic Counseling for Bladder Exstrophy-Epispadias Complex

Reutter

Holmdahl

2021

Eur J Pediatr Surg

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“…Not much is known about cloaca development in zebrafish, however, sustained Bmp signaling is needed for proper formation [ 67 ]. Recently, slc20a1a has been identified as a candidate gene for cloacal exstrophy as knockdown animals exhibit cloacal anomalies with abnormal urinary outflow [ 87 ]. In gldc deficient animals, this morphological abnormality may block fluid excretion which provides another possible explanation for the abnormal fluid homeostasis.…”

Section: Discussionmentioning

confidence: 99%

gldc Is Essential for Renal Progenitor Patterning during Kidney Development

2022

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The glycine cleavage system (GCS) is a complex located on the mitochondrial membrane that is responsible for regulating glycine levels and contributing one-carbon units to folate metabolism. Congenital mutations in GCS components, such as glycine decarboxylase (gldc), cause an elevation in glycine levels and the rare disease, nonketotic hyperglycinemia (NKH). NKH patients suffer from pleiotropic symptoms including seizures, lethargy, mental retardation, and early death. Therefore, it is imperative to fully elucidate the pathological effects of gldc dysfunction and glycine accumulation during development. Here, we describe a zebrafish model of gldc deficiency that recapitulates phenotypes seen in humans and mice. gldc deficient embryos displayed impaired fluid homeostasis suggesting renal abnormalities, as well as aberrant craniofacial morphology and neural development defects. Whole mount in situ hybridization (WISH) revealed that gldc transcripts were highly expressed in the embryonic kidney, as seen in mouse and human repository data, and that formation of several nephron segments was disrupted in gldc deficient embryos, including proximal and distal tubule populations. These kidney defects were caused by alterations in renal progenitor populations, revealing that the proper function of Gldc is essential for the patterning of this organ. Additionally, further analysis of the urogenital tract revealed altered collecting duct and cloaca morphology in gldc deficient embryos. Finally, to gain insight into the molecular mechanisms underlying these disruptions, we examined the effects of exogenous glycine treatment and observed analogous renal and cloacal defects. Taken together, these studies indicate for the first time that gldc function serves an essential role in regulating renal progenitor development by modulating glycine levels.

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“…Recently, we described SLC20A1 , encoding a sodium-phosphate symporter, as the putative monogenic dominant disease gene for isolated BEEC 7 . We were able to support our genetic data through functional studies in non-BEEC human embryos, mouse embryos, and zebrafish Morpholino knockdown experiments.…”

Section: Discussionmentioning

confidence: 99%

A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy

et al. 2022

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Classic bladder exstrophy represents the most severe end of all human congenital anomalies of the kidney and urinary tract and is associated with bladder cancer susceptibility. Previous genetic studies identified one locus to be involved in classic bladder exstrophy, but were limited to a restrict number of cohort. Here we show the largest classic bladder exstrophy genome-wide association analysis to date where we identify eight genome-wide significant loci, seven of which are novel. In these regions reside ten coding and four non-coding genes. Among the coding genes is EFNA1, strongly expressed in mouse embryonic genital tubercle, urethra, and primitive bladder. Re-sequence of EFNA1 in the investigated classic bladder exstrophy cohort of our study displays an enrichment of rare protein altering variants. We show that all coding genes are expressed and/or significantly regulated in both mouse and human embryonic developmental bladder stages. Furthermore, nine of the coding genes residing in the regions of genome-wide significance are differentially expressed in bladder cancers. Our data suggest genetic drivers for classic bladder exstrophy, as well as a possible role for these drivers to relevant bladder cancer susceptibility.

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SLC20A1 Is Involved in Urinary Tract and Urorectal Development

Cited by 25 publications

References 26 publications

Genetic Counseling for Bladder Exstrophy-Epispadias Complex

Genetic Counseling for Bladder Exstrophy-Epispadias Complex

gldc Is Essential for Renal Progenitor Patterning during Kidney Development

A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy

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