Multi-organ single-cell analysis of preferential expression of CAKUT genes

Abstract Background Congenital anomalies of the kidney and urinary tract (CAKUT) comprise a heterogeneous group of developmental disorders with diverse genetic etiologies. However, it remains unclear whether these genetic factors converge on shared cellular programs across development and tissues. Methods We analyzed the expression of 91 curated CAKUT-associated genes across publicly available single-cell RNA sequencing datasets from human fetal and adult kidney, ureter, and bladder. These data were complemented by early embryonic transcriptomic profiles to characterize temporal expression dynamics and cell-type specificity. Results During kidney development, key CAKUT genes, including EYA1, SIX1, PAX2, and FOXC1, showed strong preferential expression in mesangial and mesonephric nephron tubule epithelial cells, highlighting early roles in ureteric bud induction and branching morphogenesis. Temporal analysis identified two distinct expression patterns: an early-peak group (EYA1, SIX1, SIX2, PAX2, ITGA8) with maximal expression during early nephrogenesis followed by decline, and a late-rise group, including MUC1, with increasing expression toward adult stages. Across tissues, CAKUT genes exhibited a conserved enrichment in stromal and mesenchymal cell populations. Conclusions Our findings reveal a shared stromal–mesenchymal gene expression signature underlying CAKUT pathogenesis. These results suggest that diverse genetic perturbations may converge on early mesodermal lineage programs that are critical for ureteric bud formation and kidney patterning, providing a unifying cellular framework for understanding CAKUT.