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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.

SLC20A1 Is Involved in Urinary Tract and Urorectal Development