Phenotypes associated with this allele

• Allele Symbol: Nrl^tm1Asw
• Allele Name: targeted mutation 1, Anand Swaroop
• Allele ID: MGI:2152376
• Summary: 8 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Nrl^tm1Asw/Nrl^tm1Asw	involves: 129S1/Sv * 129X1/SvJ	MGI:5490593
hm2	Nrl^tm1Asw/Nrl^tm1Asw	involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:5806540
hm3	Nrl^tm1Asw/Nrl^tm1Asw	involves: 129S1/Sv * 129X1/SvJ * C57BL/6J	MGI:2173167
cx4	Gucy2e^tm1Gar/Gucy2e^tm1Gar Nrl^tm1Asw/Nrl^tm1Asw	involves: 129S1/Sv * 129S6/SvEvTac * 129X1/SvJ * C57BL/6	MGI:6110583
cx5	Cep290^rd16/Cep290^rd16 Nrl^tm1Asw/Nrl^tm1Asw	involves: 129S1/Sv * 129X1/SvJ * BXD24/TyJ * C57BL/6	MGI:5557980
cx6	Nrl^tm1Asw/Nrl^tm1Asw Rab28^tm1d(EUCOMM)Hmgu/Rab28^tm1d(EUCOMM)Hmgu	involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:6360459
cx7	Nrl^tm1Asw/Nrl^tm1Asw Rab28^tm1d(EUCOMM)Wtsi/Rab28^tm1d(EUCOMM)Wtsi	involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:6360460
cx8	Grk1^tm1Citb/Grk1^tm1Citb Nrl^tm1Asw/Nrl^tm1Asw	involves: 129S1/Sv * 129X1/SvJ * C57BL/6J	MGI:3041984

Genotype
MGI:5490593

hm1

• Allelic Composition: Nrl^tm1Asw/Nrl^tm1Asw
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

Adult rods are reprogrammed into cone-like cells in Nrl^tm1.1Jcco/Nrl^tm1.1Jcco and Nrl^tm1Asw/Nrl^tm1Asw retinas

vision/eye

abnormal retina photoreceptor morphology ( J:193697 )

• rods are reprogrammed into cones

nervous system

abnormal retina photoreceptor morphology ( J:193697 )

• rods are reprogrammed into cones

Genotype
MGI:5806540

hm2

• Allelic Composition: Nrl^tm1Asw/Nrl^tm1Asw
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

behavior/neurological

abnormal optokinetic reflex ( J:241970 )

• visually guided behavior testing (optokinetic reflex) shows decreased cone-mediated spatial frequency thresholds with mice losing the ability to track at 6 months of age

vision/eye

abnormal retina morphology ( J:175566 )

• abnormal retinal lamination is seen at 4 weeks of age

• abnormal intraretinal hyperreflective lesions

abnormal retina photoreceptor morphology ( J:175566 )

• retina shows aberrant photoreceptor packing, with aberrant clustering of photoreceptors with empty patches where nuclear rosettes form, and abnormal association with the retinal pigment epithelium

• abnormal buildup of material in photoreceptors is seen at the photoreceptor-retinal pigment epithelium interface

• photoreceptors are not tightly packed at the retinal pigment epithelium interface

abnormal photoreceptor outer segment morphology ( J:175566 )

• outer segment of photoreceptors appears bulbous and outer segment tips are enlarged due to an internal buildup of vacuole-like structures

• photoreceptors show an outer segment disc arrangement different from rods, with some discs showing interconnections to each other and the surrounding plasma membrane

abnormal retina cone cell morphology ( J:175566 )

• excessive S-cone photoreceptors exhibit abnormal accumulations of materials

increased retina cone cell number ( J:175566 )

• excessive S-cone photoreceptor population

retina photoreceptor degeneration ( J:175566 )

• photoreceptor degeneration is seen by 8 weeks of age

retina cone cell degeneration ( J:241970 )

• 6 month old mice have fewer cones in the inferior versus superior retinas

abnormal retina pigment epithelium morphology ( J:175566 )

• severely reduced retinal pigment epithelium interface phagocytosis of outer segment, with lack of phagosomes in the retinal pigment epithelium

abnormal eye physiology ( J:175566 )

• severely reduced retinal pigment epithelium interface phagocytosis of outer segment

abnormal electroretinogram waveform feature ( J:241970 )

• M-cone responses are decreased in 2 and 6 month old mice

pigmentation

abnormal retina pigment epithelium morphology ( J:175566 )

• severely reduced retinal pigment epithelium interface phagocytosis of outer segment, with lack of phagosomes in the retinal pigment epithelium

nervous system

abnormal retina photoreceptor morphology ( J:175566 )

• retina shows aberrant photoreceptor packing, with aberrant clustering of photoreceptors with empty patches where nuclear rosettes form, and abnormal association with the retinal pigment epithelium

• abnormal buildup of material in photoreceptors is seen at the photoreceptor-retinal pigment epithelium interface

• photoreceptors are not tightly packed at the retinal pigment epithelium interface

abnormal photoreceptor outer segment morphology ( J:175566 )

• outer segment of photoreceptors appears bulbous and outer segment tips are enlarged due to an internal buildup of vacuole-like structures

• photoreceptors show an outer segment disc arrangement different from rods, with some discs showing interconnections to each other and the surrounding plasma membrane

abnormal retina cone cell morphology ( J:175566 )

• excessive S-cone photoreceptors exhibit abnormal accumulations of materials

increased retina cone cell number ( J:175566 )

• excessive S-cone photoreceptor population

retina photoreceptor degeneration ( J:175566 )

• photoreceptor degeneration is seen by 8 weeks of age

retina cone cell degeneration ( J:241970 )

• 6 month old mice have fewer cones in the inferior versus superior retinas

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
enhanced S-cone syndrome		DOID:0090059	OMIM:268100	J:175566

Genotype
MGI:2173167

hm3

• Allelic Composition: Nrl^tm1Asw/Nrl^tm1Asw
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6J

vision/eye

abnormal retina photoreceptor morphology ( J:78692 , J:84455 )

• most mutant photoreceptor nuclei were ellipsoid and showed a distributed pattern of heterochromatin, characteristic of cones (J:78692)

• immunohistochemistry revealed normal M-opsin distribution but no rhodopsin immunoreactivity; S-opsin was detected throughout the outer segments, indicating a loss of rod and 'gain' of S- but not M-cone activity (J:78692)

• analysis of "pure-cone" retinas demonstrated that both S and M cone opsins were phosphorylated after light exposure and that cone arrestin selectively bound to light-activated, phosphorylated cone opsins (J:84455)

abnormal photoreceptor outer segment morphology ( J:78692 )

• the outer segments were significantly fewer and shorter and showed abnormal disk morphology; also, the outer segment disks were often misaligned and abnormally associated with the retinal pigment epithelium

abnormal retina outer nuclear layer morphology ( J:78692 )

• at 5 weeks, the outer nuclear layer (ONL) of the mutant retina had a normal thickness and number of nuclei but appeared to be disrupted with whorls and rosettes

• by 31 weeks, the rosettes and whorls were no longer detectable and thinning of the ONL had occurred

abnormal eye physiology ( J:174592 )

• overexpress S opsin with an abnormal distribution

abnormal cone electrophysiology ( J:78692 )

• in light-adapted conditions, the b-wave threshold was the same for wild-type and mutant mice, indicating a functional cone pathway in the mutant retina

• notably, the amplitude of the maximum light-adapted ERG b-wave for mutant mice was 2-3-fold larger relative to wild-type, indicating enhanced cone-mediated activity

• ERGs using monochromatic stimuli revealed that the amplitude of the S cone-mediated response was >6 times larger for mutant mice than for wild-type, suggesting a super-normal S-cone function; in contrast, the M-cone response was relatively unaffected

abnormal rod electrophysiology ( J:78692 , J:174592 )

• ERGs from dark-adapted mutant mice revealed a complete absence of rod function ("pure-cone" retinas) (J:78692)

• lack scotopic ERG responses (J:174592)

nervous system

abnormal retina photoreceptor morphology ( J:78692 , J:84455 )

• most mutant photoreceptor nuclei were ellipsoid and showed a distributed pattern of heterochromatin, characteristic of cones (J:78692)

• immunohistochemistry revealed normal M-opsin distribution but no rhodopsin immunoreactivity; S-opsin was detected throughout the outer segments, indicating a loss of rod and 'gain' of S- but not M-cone activity (J:78692)

• analysis of "pure-cone" retinas demonstrated that both S and M cone opsins were phosphorylated after light exposure and that cone arrestin selectively bound to light-activated, phosphorylated cone opsins (J:84455)

abnormal photoreceptor outer segment morphology ( J:78692 )

• the outer segments were significantly fewer and shorter and showed abnormal disk morphology; also, the outer segment disks were often misaligned and abnormally associated with the retinal pigment epithelium

Genotype
MGI:6110583

cx4

• Allelic Composition: Gucy2e^tm1Gar/Gucy2e^tm1Gar; Nrl^tm1Asw/Nrl^tm1Asw
• Genetic Background: involves: 129S1/Sv * 129S6/SvEvTac * 129X1/SvJ * C57BL/6

vision/eye

retina cone cell degeneration ( J:241970 )

• 6 month old mice have fewer cones in the inferior versus superior retinas

thin retina outer nuclear layer ( J:241970 )

• outer nuclear layer (ONL) is 28% thinner than in single Nrl homozygotes at 6 months of age

• treatment with an adenovirus expressing Gucy2e results in cone preservation with increased ONL thickness

abnormal electroretinogram waveform feature ( J:241970 )

• ERG indicates no discernible wave forms, with no M-cone or S-cone responses

• subretinal injection of an adenovirus expressing Gucy2e at around P41, but not at P18, fully restores retinal function and useful vision over the long-term

• mice treated with an adenovirus expressing human GUCY2D at P40 exhibit restored retinal function

behavior/neurological

abnormal optokinetic reflex ( J:241970 )

• visually guided behavior testing (optokinetic reflex) shows decreased cone-mediated spatial frequency thresholds at 6 months of age

homeostasis/metabolism

abnormal enzyme/coenzyme activity ( J:241970 )

• no retinal guanylate cyclase activity in the retina

nervous system

retina cone cell degeneration ( J:241970 )

• 6 month old mice have fewer cones in the inferior versus superior retinas

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Leber congenital amaurosis 1		DOID:0110078	OMIM:204000	J:241970

Genotype
MGI:5557980

cx5

• Allelic Composition: Cep290^rd16/Cep290^rd16; Nrl^tm1Asw/Nrl^tm1Asw
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * BXD24/TyJ * C57BL/6

vision/eye

retina photoreceptor degeneration ( J:169232 )

• mice show degeneration of photoreceptors, with rapid loss of rods, however survival of cone photoreceptors is increased compared to single Cep290 mutants, showing 4-5 rows of outer nuclear layer nuclei at 3-4 months of age, indicating a much slower cone degeneration than in single mutants and an all-cone retina in mutants

abnormal cone electrophysiology ( J:169232 )

• mice show sizeable S- and M-cone-driven ERG signals although the amplitudes are reduced compared to single Nrl homozygotes

nervous system

retina photoreceptor degeneration ( J:169232 )

• mice show degeneration of photoreceptors, with rapid loss of rods, however survival of cone photoreceptors is increased compared to single Cep290 mutants, showing 4-5 rows of outer nuclear layer nuclei at 3-4 months of age, indicating a much slower cone degeneration than in single mutants and an all-cone retina in mutants

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Leber congenital amaurosis 10		DOID:0110291	OMIM:611755	J:169232

Genotype
MGI:6360459

cx6

• Allelic Composition: Nrl^tm1Asw/Nrl^tm1Asw; Rab28^{tm1d(EUCOMM)Hmgu}/Rab28^{tm1d(EUCOMM)Hmgu}
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

vision/eye

abnormal retina cone cell outer segment morphology ( J:267522 )

• cone outer segment tips are larger than in single Nrl mutants

• no cone phagosomes are seen in the outer segment

nervous system

abnormal retina cone cell outer segment morphology ( J:267522 )

• cone outer segment tips are larger than in single Nrl mutants

• no cone phagosomes are seen in the outer segment

Genotype
MGI:6360460

cx7

• Allelic Composition: Nrl^tm1Asw/Nrl^tm1Asw; Rab28^{tm1d(EUCOMM)Wtsi}/Rab28^{tm1d(EUCOMM)Wtsi}
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

vision/eye

abnormal retina cone cell outer segment morphology ( J:267522 )

• cone outer segment tips are larger than in single Nrl mutants

• no cone phagosomes are seen in the outer segment

nervous system

abnormal retina cone cell outer segment morphology ( J:267522 )

• cone outer segment tips are larger than in single Nrl mutants

• no cone phagosomes are seen in the outer segment

Genotype
MGI:3041984

cx8

• Allelic Composition: Grk1^tm1Citb/Grk1^tm1Citb; Nrl^tm1Asw/Nrl^tm1Asw
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6J

vision/eye

abnormal retina photoreceptor morphology ( J:84455 )

• in situ light-dependent phosphorylation of opsins ex vivo showed that neither S nor M opsin was phosphorylated in the double mutant mouse retina after light exposure

• however, retinas of double mutant mice displayed the same morphology as those of single Nrl mutant mice, and both S and M opsins were expressed in the double mutant retina at equivalent levels to those in single Nrl mutant retina

nervous system

abnormal retina photoreceptor morphology ( J:84455 )

• in situ light-dependent phosphorylation of opsins ex vivo showed that neither S nor M opsin was phosphorylated in the double mutant mouse retina after light exposure

• however, retinas of double mutant mice displayed the same morphology as those of single Nrl mutant mice, and both S and M opsins were expressed in the double mutant retina at equivalent levels to those in single Nrl mutant retina