TABLE 2.
Rodent models of NPH discussed in this review.
| Species | Name | Human ortholog | Type of mutation | Renal disease progression | Survival | Tubular phenotype | Interstitial phenotype | Urine concentration defect | Kidney size | Extrarenal phenotypes | References |
| Mouse | Nphp1 | NPHP1 | Out-of-frame deletion exon 20 | NA | Normal | – | – | NA | Normal | Male infertility | Jiang et al. (2008) |
| Invs | INVS/NPHP2 | Out-of-frame deletion exon 3–11 | Rapid (kidney failure around age 1 week) | Around 1 week | Absence of tubular atrophy and tubular basement membrane irregularities; corticomedullary cysts arising from proximal tubule and collecting duct; | – | NA | Enlarged | Situs inversus, biliary obstruction/atresia | Yokoyama et al. (1993); Lowe et al. (1996); Mochizuki et al. (1998); Morgan et al. (1998); Phillips et al. (2004) | |
| Polycystic kidney disease (Pcy) | NPHP3 | Missense | Slow (kidney failure in adult mice) | NA | Tubular atrophy and tubular basement membrane thickening; corticomedullary cysts followed by entire kidney, tubular dilations arising predominantly from distal tubules and collecting duct | Tubulointerstitial fibrosis and inflammation (late stage) | NA | Enlarged | Cerebral vascular aneurysms | Takahashi et al. (1991); Omran et al. (2001); Olbrich et al. (2003) | |
| Nphp4 | NPHP4 | Missense | NA | Normal | – | – | NA | Normal | Retinal disease, male infertility | Won et al. (2011) | |
| Iqcb1 | IQCB1/NPHP5 | Gene trap leading to loss of function | NA | NA | – | – | NA | Normal | Retinal disease | Ronquillo et al. (2016) | |
| Cep290 | CEP290/NPHP6 | Gene trap inserted in intron 25 leading to premature stop codon | NA | 129/Ola background: survival past age 1 year | Small cysts in cortex arising from collecting duct | – | Evidence of polyuria and polydipsia | NA | Retinal disease, cerebral abnormalities | Hynes et al. (2014) | |
| Rd16: deletion of exons 35 to 39 | NA | NA | – | – | NA | Normal | Retinal disease | Chang et al. (2006) | |||
| Knockout | Slow | Mixed C57BL/6 and 129/SvJ background: 80% lethality within first weeks due to hydrocephalus; surviving mice lived until age 2 years | Corticomedullary cysts develop after 12 months | – | NA | Enlarged | Retinal disease, cerebral and cerebellar abnormalities | Rachel et al. (2015) | |||
| Gene trap inserted in intron 25 leading to premature stop codon | Rapid | C57BL/6 and 129/SvJ backgrounds: majority dies prenatally; mice that survive to age 2–3 weeks show severe cystic kidney disease | Loss of tubules (not further specified); corticomedullary cysts | Cellular infiltrate | NA | Enlarged | Retinal disease, hepatic pallor | ||||
| Glis2 | GLIS2/NPHP7 | Knockout | NA | >40% lethality by age 10 months | Atrophy of proximal tubules, minimal tubular basement membrane thickening; corticomedullary and glomerular cysts | Tubulointerstitial inflammation and fibrosis starting at age 8 weeks | NA | Reduced | – | Attanasio et al. (2007); Kim et al. (2008) | |
| Rpgrip1l (Ftm) | RPGRIP1L/NPHP8 | Knockout | NA | Embryonically lethal | Cortical microcysts arising from proximal tubule at 18.5 days post conception | – | NA | NA | Exencephaly, microphthalmia, situs inversus, liver abnormalities, polydactyly | Delous et al. (2007) | |
| Juvenile cystic kidneys (Jck) | NEK8/NPHP9 | Missense | NA | 100% lethality by age 25 weeks in males and age 80 weeks in females | Basement membrane disruptions; corticomedullary cysts followed by entire kidney, arising from collecting duct, in later stage also from distal tubule and loop of Henle | – | NA | Enlarged | – | Atala et al. (1993); Liu et al. (2002); Smith L. A. et al. (2006); Otto et al. (2008) | |
| Knockout | NA | Die within hours after birth due to congenital heart defect | Proximal tubule dilation; glomerular cysts and (few cysts develop in kidney explant culture) | – | NA | Normal | Situs inversus, cardiac anomalies | Manning et al. (2013) | |||
| Sdccag8 | SDCCAG8/NPHP10 | Gene trap leading to loss of function | Slow | Survival > 250 days | Initial cortical cysts followed by corticomedullary cysts, arising from distal convoluted tubule and collecting duct; glomerular cysts | Tubulointerstitial fibrosis (late stage) | NA | Enlarged (late stage) | Retinal disease | Airik et al. (2014) | |
| Bilateral polycystic kidneys (Bpck) | TMEM67/NPHP11 | Deletion | Rapid (kidney failure around age 3 weeks) | Survive to age 3 weeks | Corticomedullary cysts arising from distal tubule and collecting duct, later mild dilation of some proximal tubules | – | NA | Enlarged | Hydrocephalus, spermatogenesis defects | Cook et al. (2009) | |
| Ttc21b (Thm1) | TTC21B/NPHP12 | Loss of function mutation | NA | Embryonically lethal | Cystic dilations of glomeruli, proximal tubules and ascending loops of Henle | – | NA | NA | – | Tran et al. (2008, 2014) | |
| Conditional Ttc21b knockout using ROSA26Cre ERT+ | Rapid (cystic kidney disease and elevated BUN by age 6 weeks when Ttc21b is inactivated before P12-14) | NA | Cortical cysts arising from proximal tubule, loop of Henle and collecting duct | – | NA | Enlarged | – | Tran et al. (2014) | |||
| Cep164 | CEP164/NPHP15 | Kidney-specific Cep164 inactivation using Hoxb7-Cre (collecting duct) | Rapid (kidney failure around 3 weeks) | Median survival 25 days | Cysts in medulla followed by cortex and entire kidney, arising from collecting duct | – | NA | Enlarged | – | Airik et al. (2019) | |
| Anks6 | ANKS6/NPHP16 | Missense mutation | Slow | Survival to age 18 months | Cysts arising from collecting duct, thick ascending limb of loop of Henle, to a lesser extent from distal tubule; glomerular cysts | Interstitial fibrosis | NA | Enlarged | – | Bakey et al. (2015) | |
| Mapkbp1 | MAPKBP1/NPHP20 | Knockout | NA | Normal | – | – | NA | Normal | – | Macia et al. (2017) | |
| Ofd1 | OFD1 | Kidney-specific Ofd1 inactivation using Ksp-Cre (distal tubule and collecting duct) | Severely impaired kidney function at age 1–3 months | Animals sacrificed at age 3 months | Cysts in medulla followed by cortex, arising from distal tubules; later glomerular cysts and proximal tubular cysts | – | NA | Enlarged | – | Zullo et al. (2010) | |
| Ahi1 | AHI1 | Knockout | Slow (kidney function impairment at age 1 year or older) | 80% did not survive into adulthood | Tubular basement membrane disruption and thickening; corticomedullary microcysts and tubular dilations, mainly arising from proximal tubule | Interstitial cell infiltrate and fibrosis | Urinary concentration defect | Reduced by age 5 months | – | Lancaster et al. (2009) | |
| Non-orthologous mouse models | Fan1 | FAN1 | Knockout mice treated with 2 mg/kg cisplatin | Rapid (kidney failure within 5 weeks after start of treatment) | NA | Tubular basement membrane thickening; tubular dilation; karyomegalic nuclei in proximal tubule | Tubulointerstitial inflammation and fibrosis | NA | NA | Bone marrow failure | Airik et al. (2016) |
| Prkar1a | PRKAR1A | Kidney-specific Prka1a inactivation using Pkhd1-Cre (collecting duct) | NA | Animals sacrificed at age 3 months | Small cysts primarily arising from distal tubule and collecting duct | Interstitial fibrosis | NA | Normal (enlarged in 2/16 mice) | – | Ye et al. (2017) | |
| Lkb1 | STK11/LKB1 | Kidney-specific Lkb1 inactivation using Ksp-Cre (distal tubule and collecting duct) | Rapid (kidney failure around age 5 weeks) | 50% survival around age 11 months | Tubular basement membrane thickening, tubular dilation, corticomedullary cysts at late stage | Tubulointerstitial inflammation and fibrosis | Impaired urine concentration at age 5 weeks | Reduced size at age 5 weeks | – | Viau et al. (2018) | |
| Aatf | AATF | Kidney-specific Aatf inactivation using Ksp-Cre (distal tubule and collecting duct) | Rapid (kidney failure around age 10 weeks) | Survival 10–15 weeks | Tubular basement membrane disruption and thickening; corticomedullary cysts arising from distal tubule, later glomerular cysts | Interstitial fibrosis | Urinary concentration defect | Reduced size at age 10 weeks | – | Jain et al. (2019) | |
| Rat | Lewis polycystic kidney (LPK) | NEK8/NPHP9 | Missense | Slow (kidney failure around 12–24 weeks) | No survival beyond age 26 weeks | Corticomedullary cysts, predominantly arising from collecting duct | Tubulointerstitial inflammation and fibrosis | NA | Enlarged | – | Phillips et al. (2007); McCooke et al. (2012) |
| Wistar polycystic kidney (Wpk) | TMEM67/NPHP11 | Missense | Rapid (kidney failure around age 3 weeks) | NA | Cysts in proximal tubule and collecting duct | – | NA | Enlarged | Cerebral abnormalities, hypoplastic spleen | Gattone et al. (2004); Smith U. M. et al. (2006) | |
| Cy | ANKS6/NPHP16 | Missense | Homozygous: rapid (kidney failure around age 3 weeks) | Survive to age 3 weeks | Cysts in cortex and outer medulla | – | NA | Enlarged | – | Cowley et al. (1993); Brown et al. (2005) | |
| Missense | Heterozygous: slow | Males die of kidney failure within 1 year, females survive past 1 year | Thickened tubular basement membranes; dilatations of proximal and distal tubule and collecting duct | Tubulointerstitial fibrosis and inflammation | NA | Moderately enlarged | – | Cowley et al. (1993); Brown et al. (2005) |
Severity of the phenotype can depend on background strain. Presence of a renal phenotype was not reported for mouse models of WDR19/NPHP13, ZNF423/NPHP14, IFT172/NPHP17, DCDC2/NPHP19 and ADAMTS9/NPHP21 (Alcaraz et al., 2006; Cheng et al., 2007; Gorivodsky et al., 2009; Kern et al., 2010; Wang et al., 2011; Ashe et al., 2012; Dubail et al., 2014; Nandadasa et al., 2015; Schueler et al., 2015; Casoni et al., 2017). For CEP83/NPHP18, a cortical radial glial progenitor cell-specific conditional knockout was created that did not permit study of renal phenotypes (Shao et al., 2020). NPH can be a feature of other syndromic ciliopathies. Corresponding mouse models were not included in this table unless they were discussed in the main text. NA, not available/not reported.