Table 1. Genetic mutations causing congenital UTO.
The gene names follow the terminology in the original reference. Newer names are listed in the second column. The known or predicted function of the gene product is given in the brackets, if the full name does not already have a clear indication. In the genotypes, “T” stands for the transgene; “+” stands for a wild-type allele, “-” stands for a loss-of-function allele (presumed null); “flox” stands for the floxed allele; “lz” stands for the LacZ knock-in allele (usually a null allele for the endogenous gene). SM: Smooth muscle. SMC: Smooth muscle cell. UB: Ureteric bud. MM: Metanephric mesenchyme. VUR: Vesicoureteral reflux. UTO: Urinary tract obstruction. This is intended to be a representative list, instead of a complete list, both for animal models and for humans. This is especially true for cases with UTO as a minor component of a syndrome.
| Genes/Mutations | New gene names, Gene full names, & [Function] | Alleles and the corresponding urinary defects | Proposed or likely Mechanism | Ref |
|---|---|---|---|---|
| Ace | Angiotensin converting enzyme | Ace-/- mice: hydronephrosis, renal parenchymal atrophy. | Defective pyeloureteral peristalsis as a result of a ureter differentiation defect, a urine concentration defect/polyuria, or both. | (60) |
| Adamts-1 | A disintegrin-like &metallopeptidase with thrombospondin type 1 motif, 1 | Adamts-1-/- mice: UPJ obstruction, hydronephrosis, hydroureter, other urogenital defects. | Unclear. Excessive collagen deposit was found at UPJ. | (72) |
| Agt | Angiotensinogen | Agt-/- mice: hydronephrosis, renal parenchymal atrophy. | Defective pyeloureteral peristalsis. | (61, 62) |
| Agtr1a/b | Angiotensin II receptor, type 1 (1a & 1b) | Agtr1-/- (1a & 1b) mice: partial penetrance, hydronephrosis in older mutants, renal parenchymal atrophy. | Urinary SMC developmental Defect, renal pelvis development. | (58, 59) |
| Agtr2 | Angiotensin II receptor, type 2 | Agtr2-/- mice: limited incidence of hydronephrosis, megaureter, renal parenchymal atrophy. | Ectopic and duplicated UB. | (56, 57) |
| Aldh1a2 | Aldehyde dehydrogenase family 1 member A2 [encodes Raldh2, an enzyme in retinoic acid synthesis] | Aldh1a2-/- mice rescued by maternal retinoic acid: hydroureter & hydronephrosis | Defects in ureter maturation, especially the insertion of the ureter into the bladder. | (39) |
| Aqp2 | Aquaporin 2 [Water channel] | The cph mutants (Aqp2S256L/S256L) have polyuria and hydronephrosis. Other Aqp2 mutations also cause renal damage resembling obstructive nephropathy. | Polyuria overwhelms the pyeloureteral peristaltic machinery. | (70,73,74) |
| β-catenin | Same as Ctnnb1 [adherens junction protein, involved in Wnt signaling] | Hoxb7-CreT/+; β-catenin flox/flox mice: hydroureter & hydronephrosis. | Ectopic and supernumerary UB. | (37) |
| Bmp4 | Bone morphogenetic protein 4 | Bmp4+/- mice: hydronephrosis, hydroureter, other urinary tract defects. | Ectopic and supernumerary UB. | (33, 34) |
| Bmp5 | Bone morphogenetic protein 5 | short ear (Bmp5-/-) mice: Hydroureter & hydronephrosis. | Spatial constraints in the lower abdominal cavity affect urinary transfer. | (75, 76) |
| Calcineurin | Same as Ppp3c, protein phosphatase 3. [serine/threonine Protein phosphatase] | The Pax3-CreT/+; Cnb1flox/flox mice (with Calcineurin inactivation in the metanephric and ureteral mesenchyme): early postnatal hydronephrosis & hydroureter. | Pyeloureteral peristaltic defect, defect in urinary tract SMC development. | (4) |
| Dlgh1 | Same as Dlg1, Disk-large homolog 1 [scaffolding protein] | Dlgh1-/- mice: prenatal hydronephrosis, short ureter, and defects in the ureteral insertion into the bladder. | SM differentiation defect, ectopic UB. | (43, 44) |
| Fcgr2b & Pdcd1 | Fc receptor, IgG, low affinity IIb & Programmed cell death 1 [cell surface membrane protein of the immunoglobulin superfamily] | Some Fcgr2b-/-;Pdcd1-/- mice: hydronephrosis. | Autoimmune against UPKIIIa. | (66) |
| Fgfr2 | Fibroblast growth factor receptor 2 | Some Pax3-CreT/+; Fgfr2flox/flox mice have hydroureter. | Supernumerary UB, abnormal ureter connection | (28) |
| Foxc1/c2 | Forkhead box protein C1/C2 [transcription factor] | Foxc1-/- & Foxc1+/-,Foxc2+/- mice: duplex kidney, ureter duplication, hydroureter, hydronephrosis. | Ectopic and supernumerary UB. | (77) |
| Gata2 | GATA binding protein 2 [transcription factor] | Gata2-/- mice (with YAC rescue of hematopoietic defects): hydroureter, hydronephrosis. | Unclear. | (78) |
| Hoxa13 & Hoxd13 | Homeobox A13 and D13 [transcription factor] | Hoxa13+/-; Hoxd13-/- mice: UVJ obstruction, hydronephrosis, hydroureter, other urogenital defects. | Patterning defects. May have homeotic transformation. | (79) |
| Hspa4l | Heat shock protein 4 like [chaperone?] | Some Hspa4l-/- mice have genetic background-dependent hydronephrosis. | Unclear. | (80) |
| Id2 | Inhibitor of DNA binding 2 | Id2-/- and Id2+/- mice have hydronephrosis. | UPJ development. | (81) |
| Il-9 | Interleukin 9 | Overexpressing Il-9 by its own promoter in mice: hydronephrosis | Likely autoanitibodies against urinary tract components. | (67) |
| L1cam | L1 cell adhesion molecule | L1cam-/- mice: hydroureter & hydronephrosis. | Ectopic UB. | (82) |
| Lim1 | Same as Lhx1 – Lim homeobox protein 1 [transcription factor] | Hoxb7-CreT/+; Lim1lz/flox mice (with Lim1 deletion in the UB derivatives): hydroureter & hydronephrosis. | Ureter differentiation. | |
| Limp-2 (Lgp85) | Same as Scarb2 [scavenger receptor] | Limp-2-/- mice: kidney and ureter duplication, UPJ obstruction, hydroureter, and hydronephrosis. | Ectopic and supernumerary UB. | (83) |
| Lx (luxate) | Unknown | Some Lx+/- and -/- mice: hydroureter, hydronephrosis, horseshoe kidney. | Crossing vessels suspected (84). New results point to early metanephric patterning defects (Unpublished results from our laboratory). | (84) |
| Megabladder | Unknown | Mutants have hydronephrosis, hydronephrosis, megabladder | Bladder SM development. | (85) |
| Nfia | Nuclear factor I/A [transcription factor] | Nfia+/- and Nfia-/- mice: VUR, hydronephrosis & hydroureter. Human NFIA+/- patients have similar defects. | Abnormal development of the UPJ and UVJ. | (47) |
| Nkcc2 | Same as Slc12a1-solute carrier family 12, member 1 [Sodium-potassium-chloride cotransporter] | Nkcc2-/- mice: polyuria and hydronephrosis of varying severity. | Possibly by polyuria overwhelming the pyeloureteral peristaltic machinery. | (86) |
| Pax2 | Paired box gene 2 [transcription factor] | Pax21Neu/+ mice: VUR. Other human and mouse mutant alleles also cause VUR in addition to renal agenesis. | Delay in urinary tract maturation in the Pax21Neu/+ mice. | (45) |
| Rara/Rarb2 | Retinoic acid receptor, alpha/retinoic acid receptor beta 2 | Rara-/-;Rarb2-/- mice have hydronephrosis, hydroureter, VUR. | Defective differentiation of the MM. | (63) |
| Renin | Same as Ren1 [an enzyme in the rennin-angiotension system] | Renin-/- mice: hydronephrosis, renal parenchymal atrophy. | Possibly by polyuria. It is also possible that the mutation disrupts SM differentiation. | (87) |
| Ret | Ret proto-oncogene [Gdnf receptor] | Ret-/- mice: renal agenesis, hydronephrosis, hydroureter, VUR. | UB initiation defect, ureter maturation defect. | (36, 88, 89) |
| Mice carrying Ret alleles with specific mutation of the keytyrosines: CAKUT. | Ectopic and supernumerary UB. | (29) | ||
| Mice overexpressing Ret in UB: VUR. | Ureter maturation defect. | (90) | ||
| Robo2 | Roundabout homolog 2 [SLIT2 receptor] | Robo2-/- mice and human patients carrying ROBO2 mutations/variants have VUR. | Ectopic and supernumerary UB. | (24, 91, 92) |
| Romk | Same as Kcnj1, potassium inwardly-rectifying channel, subfamily J, member 1 | Romk-/- mice: hydronephrosis, water and electrolyte balance problem. | Unclear. | (93) |
| Shh | Sonic hedgehog [secreted signaling molecule] | Hoxb7-CreT/+; Shhflox/flox mice (Shh-/- in UB derivatives): hydroureter & hydronephrosis. | Mesenchymal proliferation, SMC differentiation. | (52) |
| Slc7a9 | Solute carrier family 7 member 9 [cationic amino acid transporter] | Slc7a9-/- mice: cystine urolithiasis and hydroureter. | Urolithiasis blocks urine flow. Not strictly “congenital”. | (71) |
| Slit2 | Slit homolog 2 [ROBO2 ligand] | Slit2-/- mice: hydroureter and hydronephrosis. | Ectopic and supernumerary UB. | (24) |
| Smad4 | MAD homolog 4 [Tgfβ signal transducer] | Bmp7-CreT/+; Smad4flox/flox mice: hydronephrosis, | Defective MM differentiation. | (94) |
| Spry1 | Sprouty homolog 1 [RTK/ERK antagonist] | Spry1-/- mice: hydroureter and hydronephrosis. | Ectopic and supernumerary UB. | (31) |
| Spry2 | Sprouty homolog 2 [RTK/ERK antagonist] | Spry2-/- mice: renal agenesis, Hydroureter and hydronephrosis. | Ectopic and supernumerary UB. | (95) |
| Tbx18 | T-box transcription factor 18 | Tbx18-/- mice: hydronephrosis, hydroureter, and short ureters. | Ureteral SM defects due to ureteric mesenchyme differentiation anomalies. | (42) |
| Tensin | Same as Tns1 [actin-binding protein] | Tensin-/- mice: cystic and hydronephrotic kidney at a few months of age. | Unclear, cell-cell, cell matrix interaction? | (96) |
| Tshz3 | Teashirt zinc finger family member 3 [transcription factor] | Tshz3-/- mice: hydronephrosis and hydronephrosis. | Defects in ureteral SM differentiation. | (53) |
| UpkII | Uroplakin II [Glycolsylated Transmembrane protein] | UpkII-/- mice: hydronephrosis, hydroureter, VUR. | Urothelial hyperplasia may block the urinary path. Alternatively, the urothelium defects may affect SM development. | (63) |
| UpkIII | Uroplakin III [Glycolsylated Transmembrane protein] | UpkIII-/- mice: hydronephrosis, hydroureter, VUR. | Urothelial hyperplasia may block the urinary path. Alternatively, the urothelium defects may affect SM development. | (64) |