TABLE 7.
Genetically modified rat models of human genetic diseases.
| System/organ affected | Human genetic disease | Gene/genetic modification | Genomic tool used | References | Rats vs. mice | Depository or breeder company ID |
| Cardiovascular | pulmonary arterial hypertension | BMPR2/KO | ZFN | Ranchoux et al., 2015; Hautefort et al., 2019; Manaud et al., 2020 | Bmpr2KO rats showed pulmonary vascular cell phenotypes closer to human patients than inBmpr2 KOmice | RGD#38501086 (not available) RGD #14975305 #14981588 |
| Primary pulmonary hypertension 4 (PPH4) | Kcnk3/KO | CRISPR-Cas9 | Lambert et al., 2019 | Rats have a Kcnk3 gene as humans do but mice do not | / | |
| Atrial fibrillation, familial, 18 (ATFB18) | Myl4/KO | CRISPR-Cas9 | Peng et al., 2017 | This model reproduces the human disease NoMyl4/KO mouse model is reported | / | |
| Familial hypertrophic cardiomyopathy and myocardial genetic diseases | Myh7b/KO | CRISPR-Cas9 | Chen et al., 2020 | This model reproduces the human disease No Myh7b/KO mouse model is reported | / | |
| Danon disease | Lamp2/KO | TALEN | Wang et al., 2017; Ma S. et al., 2018 | Lamp2-KO rats could be a more valuable animal model for DD than Lamp2/KO mice | RGD #13703119 | |
| Nervous system | Epileptic encephalopathy, early infantile, 63 (EIEE63) | Cplx1/KO | CRISPR-Cas9 | Xu et al., 2020 | Cplx1/KO rats and mice show different phenotypes Rat model reproduces the disease better | |
| Dystonia 25 (DYT25) | Gnal/KO | CRISPR-Cas9 | Yu-Taeger et al., 2020 | Gnal/KO rats show early symptoms as in patients not seen inGnal/KO mice | / | |
| Cockayne syndrome | Ercc6/KO (KI R571X) | CRISPR-Cas9 | Xu et al., 2019 | The brain is more affected in CSB-deficient rats vs. mice | / | |
| Neonatal hydrocephalus | L1cam/KO | CRISPR-Cas9 | Emmert et al., 2019b | L1cam/KO rats and mice show similar phenotypes similar to those of patients | RRRC #850 + 851 | |
| Ccdc39/KI point mutation c.916+2T | CRISPR-Cas9 | Emmert et al., 2019a | Ccdc39KO rats and mice show similar phenotypes Rats are more suitable for imaging and surgical experiments | / | ||
| Schizophrenia | Drd2/KI reporter | CRISPR-Cas9 | Yu et al., 2016 | Inter-species difference of DRD2 expression between rats and mice | / | |
| Amyotrophic lateral sclerosis | Fus/KI point mutation R521C | CRISPR-Cas9 | Zhang T. et al., 2018 | Fus/KI rats and mice show an altered phenotype with subtle differences | / | |
| Neurofibromatosis type 1 | Nf1/KO | CRISPR-Cas9 | Moutal et al., 2017; Dischinger et al., 2018 | Nf1/KO rats have a more pronounced phenotype than Nf/ KO mice | / | |
| Cystic leukoencephalopathy | RNaseT2/KO BigDel | CRISPR-Cas9 | Sinkevicius et al., 2018 | No RNaseT2/KO mice reported | RGD #13781890, not available | |
| Epileptic encephalopathy, early infantile, 24 (EIEE24) | Hcn1/KO | TALEN | Nishitani et al., 2019 | Hcn1/KO rats but not Hcn1/KO mice exhibited epilepsy | NBRP Rat #0821 #0820 #0819 #0822 | |
| MECP2-related severe neonatal encephalopathy, Rett-like syndrome (RTT) | Mecp2/KO | ZFN | Engineer et al., 2015 | Mecp2/KO rats displayed more symptoms of RTT than KO mice | RGD #11567272; Horizon Discovery | |
| Fragile X syndrome/Asperger syndrome, X-linked, 1 (ASPGX1) | Fmr1/Nlgn3/DKO | ZFN | Hamilton et al., 2014 | Similar phenotype for Fmr1/Nlgn3/DKO rats and mice. Rats more suitable than mice for analysis of complex behavioral and social activities | RGD #11568700; Horizon Discovery; Nlgn3) RGD #11568040; Horzon Discovery; Fmr1 KO; RGD #11553873 | |
| Phelan-McDermid syndrome | Shank3/KO Shank3/KO BigDel | ZFN CRISPR-Cas9 |
Harony-Nicolas et al., 2017 Song et al., 2019 |
Shank3-KO rats showed normal social interaction and self-grooming behaviors whereas Shank3-KO mice do not | / | |
| Angelman syndrome | Ube3A/KO BigDel | CRISPR-Cas9 | Dodge et al., 2020 | As in patients, Ube3A/KO ratsbear a large deletion of the gene whereasUbe3A/KOmice not | / | |
| Intellectual deficiency from genetic origin | Cplx1/KO | CRISPR-Cas9 | Xu et al., 2020 | Cplx1/KO rats showed ataxia, dystonia, exploratory deficits, anxiety and sensory deficits but normal cognitive function | / | |
| Essential tremor | Aspa and Hcn1/KO | TALEN | Nishitani et al., 2020 | Aspa and Hcn1/KO rats developed tremor | NBRP Rat #0806 #0805 (Aspa KO); Cf Table 6 pour Hcn1 KO | |
| Ataxia-telangiectasia | Atm/KO | ZFN | Quek et al., 2017 | Atm/KO rats show cerebellar atrophy and neurodegeneration which are poorly recapitulated in Atm/KO mice | NBRP #0627 #0649 | |
| Autism spectrum disorder | Cntnap2/KO | ZFN CRISPR | Scott et al., 2018 | Cntnap2/KO rats better recapitulate certain behavioral symptoms thando Cntnap2/KO mice | RGD #11568646; Horizon Discovery; RGD #25330087 (CRISPR); | |
| Shank2/KO | ZFN | Modi et al., 2018 | Shank2/KO rats show behavior and electroencephalography abnormalities not seen inShank2/KO mice | / | ||
| Canavan disease | Aspa/KO | TALEN | Nishitani et al., 2016 | Aspa/KO rats and mice show similar phenotypes similar to those of patients | NBRP Rat #0806 #0805 | |
| Familial focal epilepsy | Depdc5/KO | TALEN | Marsan et al., 2016 | Homozygous Depdc5/KO rats and mice have similar phenotypes but heterozygous Depdc5/KO rats and not mice had altered neuron excitability and firing patterns | NBRP Rat #0739 | |
| Parkinson’s disease | Lrrk2/KO | ZFN | Ness et al., 2013 | LrrK2/KO rats and mice show similar phenotypes similar to those of patients | RGD #7241053; Lrrk1/Lrrk2 KO Horizon Discovery RGD #7241047; Lrrk1/Lrrk2 KO Horizon Discovery RGD #7241050; Lrrk2/KO; Horizon discovery RGD #7241056; Lrrk2/KO; Horizon Discovery | |
| Alpha-synuclein autosomal dominants forms of Parkinson’s disease | SNCA-A53T-A30P/Tg | DNA microinjection | Lelan et al., 2011 | SNCA-A53T transgenic rats and mice have similar phenotypes | / | |
| Familial Parkinson’s disease | DJ-1 and Pink1/KO | ZFNs | Sun et al., 2013 | DJ-1 and Pink1/KO rats and mice show similar phenotypes similar to those of patients | DJ-1 RGD #7241054 + RGD #7241049 Pink1/KO; Horizon discovery | |
| congenital generalized lipodystrophy | Bscl2/KO | ENU | Ebihara et al., 2015 | Bscl2/KO rats have brain reduction and azoospermia as in patients, Bscl2/KO mice do not reproduce these pathologies | NBRP Rat #0763 | |
| Autosomal-dominant lateral temporal lobe epilepsy | LGI1/KO | ENU | Baulac et al., 2012 | Rats reproduce the human disease and are complementary to the KO mice | NBRP Rat #0656 | |
| Gastrointestinal | Hereditary tyrosinemia type I | Fah/KO | CRISPR | Zhang et al., 2016 | Fah/KO rats developed liver fibrosis and cirrhosis, not observed in Fah/KO mutant mice | RGD #10002791 (TALEN; PhysGenKO) RGD #14398825 (CRISPR) RGD #14398828 (CRISPR |
| Hirschsprung disease | Ednrb/KO | CRISPR-Cas9 | Wang et al., 2019a | Ednrb/KO rats in a particular strain caused embryonic lethality and megacolon as in certain strains of Ednrb/KO mice | / | |
| Rotor syndrome | OATP1B2/KO | CRISPR-Cas9 | Ma et al., 2020 | OATP1B2/KO rats reproduce the hyperbilirubinemia observed in patients | / | |
| Atypical hereditary non-polyposis colorectal cancer | Msh6/KO | ENU mutagenesis | van Boxtel et al., 2008 | Msh6/KO develop a spectrum of tumors | / | |
| familial colon cancer | Apc/KO | ENU mutagenesis | Amos-Landgraf et al., 2007 | Apc/KO recapitulates pathology better than mouse models | RRRC#00782 + RRRC#718 (Amos-Landgraf) NBRP Rat #0443 | |
| Muscle | Muscular dystrophy (Duchenne and Becker forms) | Dmd/KO and BigDel | TALENs and CRISPR-Cas9 | Larcher et al., 2014; Nakamura et al., 2014 | Dmd/KOrats better recapitulate the pathology than Dmd/KO mice | NBRP Rat #0779 NBRP Rat #0780 NBRP Rat #0781 RGD #12880037; (TRIP) |
| Myostatin-related muscle hypertrophy | Mstn/KO | ZFN | Mendias et al., 2015; Gu et al., 2016 | In contrast to Mstn/KO mice, Mstn/KO rats showed higher muscle fiber contractibility and lifelong increase in weight in male but not female | RGD #5131964 (PhysGen KO) RGD #5143985 (PhysGenKO) RGD #5131954 (PhysGen KO) | |
| Lung | Cystic fibrosis | Cftr/KO | ZFN | Tuggle et al., 2014 | Cftr/KO rat and mice show similar phenotypes that are mostly similar to those in patients. Rats but not mice have tracheal and bronchial submucosal glands. | RGD #14392817 (SAGE, not available) RGD #14392813; Horizon discovery RGD #14392815; Horizon discovery |
| Cftr/KO and DF508 | CRISPR-Cas9 | Dreano et al., 2019 | Cftr/KO and DF508rats and mice show similar phenotypes. DF508rats and mice show phenotypes that are milder than in their Cftr/KO counterparts. Rats but not mice have tracheal and bronchial submucosal glands | / | ||
| CFTR/KI and G5551D | ZFN | Birket et al., 2020 | CFTR/KI G5551D humanized rats display normalization of several pulmonary parameters after ivacaftor treatment | / | ||
| Endocrine | Glucocorticoid resistance | Nr3c1/cKO | CRISPR-Cas9 | Scheimann et al., 2019 | Nr3c1/cKO in CNS specific brain regions using injection of AAV-Cre vectors not possible in mice | / |
| Estrogen resistance (ESTRR) | Esr1/KOandEsr2/KO | ZFN | Rumi et al., 2014; Khristi et al., 2019 | Esr1/KOrats and mice show similar phenotypes similar to those of patients | RRRC#701 (Esr1 KO) RRRC#849 (Esr1 KO) RRRC#742 (Esr2 KO) RRRC#677 (Esr2 KO) | |
| Congenital hypothyroidism | Tshr/KO | CRISPR-Cas9 | Yang et al., 2018 | Tshr/KO rats and certain strains ofTshrKO mice show similar phenotypes similar to those of patients | / | |
| Allan-Herndon Dudley-syndrome | Mct8/KO | CRISPR-Cas9 | Bae et al., 2020 | Mct8/KO rats showed growth and reduced sperm motility and viability Mct8/KO mice did not show growth retardation | / | |
| Metabolic | Congenital leptin deficiency | Lep/KO | CRISPR-Cas9 | Guan et al., 2017 | Lep/KO rats and mice show similar phenotypes similar to those of patients | / |
| Leptin receptor deficiency | Lepr/KO | CRISPR-Cas9 and TALEN | Bao et al., 2015; Chen Y. et al., 2017 | Lep/KO rats and mice show similar phenotypes similar to those of patients | / | |
| Aceruloplasminemia | Cp/KO | CRISPR-Cas9 | Kenawi et al., 2019 | Cp/KO rats show similar plasma biochemical alterations and profile of iron overload in liver and spleen as in humans Cp/KO mice showed different results | RGD #38501060 #38501061 #38501059; not available | |
| Multiple mitochondrial dysfunctions syndrome, among them pulmonary artery hypertension | Nfu1/KI point mutation G206C | CRISPR-Cas9 | Niihori et al., 2020 | Nfu1/KI point mutation G206C is only reported in rats. The model shows both mitochondrial dysfunction, and pulmonary artery hypertension with more prevalence in females than in males, as in patients | / | |
| Generalized arterial calcification of infancy and pseudoxanthoma elasticum | Abcc6/KO | ZFN | Li et al., 2017 | Abcc6/KO rats allowed ex vivo perfusion of liver and spleen and definition of the liver as the primary site of the disease | RGD #13792683 #13792682 #10413850 #10413852 #10413854 #10413858 #10413856 | |
| Diabetes mellitus, non-insulin-dependent, 5 (NIDDM5) | AS160 (TBC1D4)/KO | CRISPR-Cas9 | Arias et al., 2019 | AS160-KOrats and mice showed similar alterations in whole body assessment Rats’ bigger size allowed measurements using single myofibers | RGD #38596327 | |
| multiple mitochondrial dysfunctions syndrome | Isca1/KI-mCherry-Cre | CRISPR-Cas9 | Yang et al., 2019 | Developmental block in embryos at 8.5 days Not reported in mice | / | |
| Primary hyperoxaluria type 1 (PH1) | Agxt/KO | CRISPR-Cas9 | Zheng et al., 2020 | Agxt/KO rat model better recapitulate the disease than the Agxt/KOmice | / | |
| Agxt/KI mutation D205N | CRISPR-Cas9 | Zheng et al., 2018 | Agxt/KI mutation D205N model recapitulates the disease in rats Not reported in mice | / | ||
| Familial hypercholesterolemia | Ldlr-ApoE/DKO | CRISPR-Cas9 and CRISPR-Cpf1 | Zhao et al., 2018; Lee J. G. et al., 2019 | DoubleLdlr-ApoE/DKO rats better recapitulate the pathology than do doubleLdlr-ApoE/DKO mice | / | |
| Dwarfism | Ghsr/Tg Ghsr/KO | DNA microinjection ENU mutagenesis |
Flavell et al., 1996 Shuto et al., 2002 |
Dwarfism in rats as in GshR/KO mice Analysis of the role of GSHR in behavioral pathologies including eating disorders | RGD #12910127 RGD #1642278 (PhysGen) RRRC#421RRRC #405 | |
| Ghsr/KO | CRISPR-Cas9 | Zallar et al., 2019 | RRRC#827 | |||
| Hyaline fibromatosis syndrome | Antxr2/KO | CRISPR-Cas9 | Liu X. et al., 2017 | Antxr2/KO rats and mice show similar phenotype Antxr2/KO rats did not develop hypertension | / | |
| Obesity (OBESITY) | Mc3R-Mc4R/DKO | CRISPR-Cas9 | You et al., 2016 | DoubleMc3R-Mc4R/DKO rats better recapitulate the pathology than do doubleMc3R-Mc4R/DKO mice | RGD #13825199 (Mc4R KO) (Hubrecht Laboratory, Centre for Biomedical Genetics, 3584 CT Utrecht, The Netherlands. Hera Biolabs, Taconic.) | |
| Congenital hyperinsulinism | Sur1/KO | TALEN | Zhou et al., 2019 | Sur1/KO rats and mice reproduce the disease Rats showed a particular glucose control profile | / | |
| Fumarase deficiency | Fh/KO | TALEN | Yu et al., 2019 | Fh/KO rats and mice show similar phenotype and reproduce the disease | RGD #13792795 #13792794 (not available) | |
| Fabry disease | Gla/KO | CRISPR-Cas9 | Miller et al., 2018 | Gla/KO rats better recapitulate the pathology than do Gla/KO mice | RGD #10054398 | |
| Oculocutaneous albinism type 1 | Tyr/KO | TALEN | Mashimo et al., 2013 | Tyr/KO rats and mice show similar phenotype and reproduce the disease | NBRP Rat #0666 | |
| Wolfram syndrome | Wfs1/KO | ZFN | Plaas et al., 2017 | Wfs1/KOrats better recapitulate the pathology than Wfs1/KO mice | / | |
| Nephrology | Focal segmental glomerulosclerosis 2 (FSGS2) | Trpc6/KO BigDel | CRISPR-Cas9 | Kim E. Y. et al., 2018 | Trpc6/KO rats and mice were protected from FSGS2 | RGD #11553908 #11553912 #11553902 |
| C3 glomerulopathy | C3/KO C3/KO | ZFN CRISPR-Cas9 | Negishi et al., 2018) Xu et al., 2018 | C3/KO rats and mice display a similar phenotype Most mouse strains have a defective complement system downstream of C3 | / RGD #19165133 | |
| REN-related kidney disease | Ren/KO | ZFN | Moreno et al., 2011 | Rats like humans have 1 copy of the Ren gene whereas mice have 2 copies Rats faithfully recapitulate the disease | RGD #4139880 (PhysGen) | |
| Ophthalmology | Autosomal dominant congenital stationary night blindness and retinitis pigmentosa | Rho s334ter/Tg | DNA microinjection | Liu et al., 1999 | This is a unique widely used model of this disease | |
| Retinitis pigmentosa 85 (RP85) | Ahr/KO | ZFN | Harrill et al., 2013 | Ahr/KO rats and mice showed distinct phenotypes in the eye, liver and kidneys during normal development and toxic responses | Cf Table 6 | |
| Autosomal dominant congenital stationary night blindness | Pde6b/KO | CRISPR-Cpf1 | Yeo et al., 2019 | Pde6b /KO rats and mice reproduce the disease Slower progression and larger anatomic architecture in rats are advantages versus the mouse model | / | |
| Familial exudative vitreoretinopathy | Lrp5/KO | CRISPR-Cas9 | Ubels et al., 2020 | Lrp5/KOrats show retinal and bone abnormalities Similar phenotype inLrp5/KOmice | / | |
| Cancer | Li-Fraumeni syndrome | Tp53 | ES ZFN | McCoy et al., 2013 | Tp53/KO rats developed more diverse tumors and more frequently than Tp53/KO mice | RGD #12904897 (Horizon Discovery) RGD #11553886NBRP Rat #0726 RRRC #00485 (ES) |
| Immune and hematological systems | Von Willebrand disease | Vwf/KO BigDel | CRISPR-Cas9 | Garcia et al., 2020 | Vwf/KO rats and mice display a similar phenotype | RGD #18182946 #39128242 #18182944 |
| Hemophilia A | F8/KO | ZFN | Nielsen et al., 2014 | F8/KO rats and mice show similar phenotype | RGD #11531094 (Novo Nordisk, Maaloev, Denmark) | |
| F8/KO (gene inversion) | CRISPR-Cas9 | Shi et al., 2020 | RGD #13800746 | |||
| ALSP | Csf1r/KO | ES cells | Pridans et al., 2018 | Csf1r/KO rats showed a more severe phenotype than patients and Csf1r/KO mice an even stronger one | / | |
| SCID | Rag1/KO | Meganucleases and CRISPR-Cas9 | Tsuchida et al., 2014; Zschemisch et al., 2012; Ménoret et al., 2013 | Rag1/KO rats and mice show similar phenotype | Cf Table 6 | |
| Rag2/KO | CRISPR-Cas9 | Liu Q. et al., 2017; Noto et al., 2018 | Rag2/KO rats and mice show similar phenotype | Cf Table 6 | ||
| Prkdc/KO | CRISPR-Cas9 | Mashimo et al., 2012; Ma et al., 2014a | Prkdc/KO rats and mice show similar phenotype | Cf Table 6 | ||
| X-linked SCID | Il2Rg/KO | ZFN, TALEN and CRISPR-Cas9 | Mashimo et al., 2012; Samata et al., 2015; Kuijk et al., 2016; Ménoret et al., 2018 | Il2rg/KO rats and mice show similar phenotype | Cf Table 6 | |
| APECED | Aire/KO | TALEN | Ossart et al., 2018 | Aire/KO rats showed a more pronounced phenotype than Aire/KO mice | Cf Table 6 | |
| Agammaglobulinemia non-Bruton type | Ighm/KO | TALEN CRISPR-Cas9 | Ménoret et al., 2010; Panzer et al., 2018 | Ighm/KO rats and mice show similar phenotype | Cf Table 6 |