RESUMO
BACKGROUND: Multicystic dysplastic kidney (MCDK) is a common form of congenital kidney anomaly. The cause of MCDK is unknown. We investigated whether MCDK in children is linked to cytogenomic aberrations. METHODS: We conducted array comparative genomic hybridization (aCGH) in ten unrelated children with MCDK. The pattern of inheritance was determined by real-time PCR in patients and their biological parents. RESULTS: Pathogenic aberrations were detected in three patients: a deletion at 7p14.3 with a size of 2.07 Mb housing 12 genes, including BBS9 (Bardet-Biedl syndrome 9) and BMPER (BMP binding endothelial regulator); a duplication at 16p13.11p12.3 with a size of 3.28 Mb that included >20 genes; and monosomy X for a female patient. The deletion at 7p14.3 was inherited from the patient's father, while the duplication at 16p13.11p12.3 was derived from the patient's mother. CONCLUSIONS: Up to 30% of patients with MCDK possess cytogenomic aberrations. BBS9 and BMPER variants have been reported to result in cystic kidney dysplasia, suggesting a possible pathogenic function for the deletion at 7p14.3 in children with MCDK. The duplication at 16p13.11p12.3 was not reported previously to associate with MCDK. Both variations were inherited from parents, indicating hereditary contributions in MCDK. Thus, aCGH is an informative tool to unravel the pathogenic mechanisms of MCDK. IMPACT: Cytogenomic aberrations are common in children with MCDK. Cytogenomic aberrations are inherited from parents, indicating hereditary contributions in MCDK. aCGH is a valuable tool to reveal pathogenic mechanisms of MCDK.
Assuntos
Síndrome de Bardet-Biedl , Rim Displásico Multicístico , Síndrome de Bardet-Biedl/patologia , Proteínas de Transporte/genética , Criança , Hibridização Genômica Comparativa , Feminino , Humanos , Rim/patologia , Rim Displásico Multicístico/genética , Rim Displásico Multicístico/patologiaRESUMO
Nephron induction during kidney development is driven by reciprocal interactions between progenitor cells (NPCs) of the cap mesenchyme (CM) and the ureteric bud (UB). The prorenin receptor (PRR) is a receptor for renin and prorenin, and an accessory subunit of the vacuolar proton pump V-ATPase. Previously, we demonstrated that conditional ablation of the PRR in Six2+ NPCs in mice (Six2PRR-/- ) causes early neonatal death. Here, we identified genes that are regulated by PRR in Six2+ NPCs FACS-isolated from Six2PRR-/- and control kidneys on embryonic day E15.5 using whole-genome expression analysis. Seven genes with expression in CM cells previously shown to direct kidney development, including Notch1, ß-catenin, Lef1, Lhx1, Jag1, and p53, were downregulated. The functional groups within the downregulated gene set included genes involved in embryonic and cellular development, renal regeneration, cellular assembly and organization, cell morphology, death and survival. Double-transgenic Six2PRR-/- /BatGal+ mice, a reporter strain for ß-catenin transcriptional activity, showed decreased ß-catenin activity in the UB in vivo. Reduced PRR gene dosage in heterozygous Six2PRR+/- mice was associated with decreased glomerular number, segmental thickening of the glomerular basement membrane with focal podocyte foot process effacement, development of hypertension and increased soluble PRR (sPRR) levels in the urine at 2 months of age. Together, these data demonstrate that NPC PRR performs essential functions during nephrogenesis via control of hierarchy of genes that regulate critical cellular processes. Both reduced nephron endowment and augmented urine sPRR likely contribute to programming of hypertension in Six2PRR+/- mice.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hipertensão , Néfrons/embriologia , Néfrons/metabolismo , Receptores de Superfície Celular/metabolismo , Células-Tronco/metabolismo , Animais , Rim/embriologia , Camundongos , Camundongos Knockout , Organogênese , Receptor de Pró-ReninaRESUMO
The prorenin receptor (PRR) is a receptor for renin and prorenin, and an accessory subunit of the vacuolar proton pump H+-ATPase. Renal branching morphogenesis, defined as growth and branching of the ureteric bud (UB), is essential for mammalian kidney development. Previously, we demonstrated that conditional ablation of the PRR in the UB in PRRUB-/- mice causes severe defects in UB branching, resulting in marked kidney hypoplasia at birth. Here, we investigated the UB transcriptome using whole genome-based analysis of gene expression in UB cells, FACS-isolated from PRRUB-/-, and control kidneys at birth (P0) to determine the primary role of the PRR in terminal differentiation and growth of UB-derived collecting ducts. Three genes with expression in UB cells that previously shown to regulate UB branching morphogenesis, including Wnt9b, ß-catenin, and Fgfr2, were upregulated, whereas the expression of Wnt11, Bmp7, Etv4, and Gfrα1 was downregulated. We next demonstrated that infection of immortalized UB cells with shPRR in vitro or deletion of the UB PRR in double-transgenic PRRUB-/-/BatGal+ mice, a reporter strain for ß-catenin transcriptional activity, in vivo increases ß-catenin activity in the UB epithelia. In addition to UB morphogenetic genes, the functional groups of differentially expressed genes within the downregulated gene set included genes involved in molecular transport, metabolic disease, amino acid metabolism, and energy production. Together, these data demonstrate that UB PRR performs essential functions during UB branching and collecting duct morphogenesis via control of a hierarchy of genes that control UB branching and terminal differentiation of the collecting duct cells.