Phenotypes associated with this allele

• Allele Symbol: Gucy2e^tm1Gar
• Allele Name: targeted mutation 1, David L Garbers
• Allele ID: MGI:2183212
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Gucy2e^tm1Gar/Gucy2e^tm1Gar	involves: 129S6/SvEvTac	MGI:3711277
hm2	Gucy2e^tm1Gar/Gucy2e^tm1Gar	involves: 129S6/SvEvTac * C57BL/6	MGI:3693895
cx3	Gucy2e^tm1Gar/Gucy2e^tm1Gar Nrl^tm1Asw/Nrl^tm1Asw	involves: 129S1/Sv * 129S6/SvEvTac * 129X1/SvJ * C57BL/6	MGI:6110583
cx4	Gucy2e^tm1Gar/Gucy2e^tm1Gar Gucy2f^tm1Wbae/Gucy2f^tm1Wbae	involves: 129S6/SvEvTac	MGI:3711279

Genotype
MGI:3711277

hm1

• Allelic Composition: Gucy2e^tm1Gar/Gucy2e^tm1Gar
• Genetic Background: involves: 129S6/SvEvTac

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

Ultrastructure of wild type and degenerative Gucy2e^tm1Gar/Gucy2e^tm1Gar cone outer segments

vision/eye

abnormal retina cone cell morphology ( J:120903 )

• at distal connecting cilia, membrane components are partitioned into layered stacks

abnormal retina cone cell inner segment morphology ( J:120903 )

• apical inner segments of cones appear retracted from connecting cilia and surrounded by extracellular blebs

abnormal retina cone cell outer segment morphology ( J:120903 )

• at 2 months of age, cone outer segments (COS) in retinas are extremely disorganized

retina degeneration ( J:120903 )

• in severely degenerated cases, membranes are detached

abnormal eye physiology ( J:120903 )

• sensitivity of rods to light (half-saturating flash intensity of 13.6 photons/um²) is 3.5-fold higher than wild-type

abnormal eye electrophysiology ( J:120903 )

abnormal rod electrophysiology ( J:120903 )

• scotopic a- and b-wave amplitudes in 4-6 week old mice are significantly reduced compared to wild-type responses

• after exposure to high intensity light, followed by 1 hour of dark adaptation, a-wave amplitude recovery is delayed relative to wild-type, with only 30% recovery

nervous system

abnormal retina cone cell morphology ( J:120903 )

• at distal connecting cilia, membrane components are partitioned into layered stacks

abnormal retina cone cell inner segment morphology ( J:120903 )

• apical inner segments of cones appear retracted from connecting cilia and surrounded by extracellular blebs

abnormal retina cone cell outer segment morphology ( J:120903 )

• at 2 months of age, cone outer segments (COS) in retinas are extremely disorganized

Genotype
MGI:3693895

hm2

• Allelic Composition: Gucy2e^tm1Gar/Gucy2e^tm1Gar
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6

vision/eye

decreased retina cone cell number ( J:77627 )

• by 5 weeks of age, number of identifiable cones is dramatically reduced

retina cone cell degeneration ( J:77627 )

• cells degenerate rapidly at 4-5 weeks of age, with few surviving at late stages

abnormal eye electrophysiology ( J:77627 )

• by 1 month of age, electroretinograms (ERG) of mutant mice are abnormal

abnormal cone electrophysiology ( J:77627 )

• at one month of age, cone responses to flashes in rod-saturating background are barely detectable

abnormal rod electrophysiology ( J:77627 )

• rod a-wave and b-wave of ERG are severely reduced at one month of age

• flash response from a rod demonstrates increased time-to-peak before decaying more rapidly than in controls; rods have a higher sensitivity than wild-type

• rods show oscillations during and after recovery from a light flash

nervous system

decreased retina cone cell number ( J:77627 )

• by 5 weeks of age, number of identifiable cones is dramatically reduced

retina cone cell degeneration ( J:77627 )

• cells degenerate rapidly at 4-5 weeks of age, with few surviving at late stages

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
cone-rod dystrophy 6		DOID:0111011	OMIM:601777	J:77627

Genotype
MGI:6110583

cx3

• 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:3711279

cx4

• Allelic Composition: Gucy2e^tm1Gar/Gucy2e^tm1Gar; Gucy2f^tm1Wbae/Gucy2f^tm1Wbae
• Genetic Background: involves: 129S6/SvEvTac

Abnormal rod outer segments in Gucy2e^tm1Gar/Gucy2e^tm1Gar Gucy2f^tm1Wbae/Gucy2f^tm1Wbae mice

vision/eye

decreased retina cone cell number ( J:120903 )

♀ • retinas have slightly decreased cone numbers relative to controls

short photoreceptor outer segment ( J:120903 )

♀ • at 2 months of age, outer segment lengths are ~50-70% of normal

abnormal retina cone cell outer segment morphology ( J:120903 )

♀ • cone cell remnants are identified in the retina, but outer segments are absent

retina cone cell degeneration ( J:120903 )

♀ • cone degeneration is most severe inferior to the optic nerve

abnormal retina rod cell morphology ( J:120903 )

♀ • complete lack of cGMP

♀ • rods are surrounded by blebs in interphotoreceptor matrix

short retina rod cell outer segment ( J:120903 )

♀ • at 6 months of age, rod outer segments are severely reduced in superior/inferior and nasal/temporal quadrants

♀ • in retina, rod outer segments are shorter and narrower than in wild-type, and appear banded by alternating regions of dense membrane layers and lumen-containing tubules

thin retina outer nuclear layer ( J:120903 )

♀ • at 6 months of age, outer nuclear layer (ONL) contains only 4-6 rows of nuclei

abnormal rod electrophysiology ( J:120903 )

♀ • scotopic electroretinographic responses are absent in all double homozygotes

♀ • no detectable light-sensitive current is detectable in rods

♀ • after exposure to high intensity light, followed by 1 hour of dark adaptation, a-wave amplitude recovery is completely absent in mutants compared to 70% recovery in wild-type

nervous system

decreased retina cone cell number ( J:120903 )

♀ • retinas have slightly decreased cone numbers relative to controls

short photoreceptor outer segment ( J:120903 )

♀ • at 2 months of age, outer segment lengths are ~50-70% of normal

abnormal retina cone cell outer segment morphology ( J:120903 )

♀ • cone cell remnants are identified in the retina, but outer segments are absent

retina cone cell degeneration ( J:120903 )

♀ • cone degeneration is most severe inferior to the optic nerve

abnormal retina rod cell morphology ( J:120903 )

♀ • complete lack of cGMP

♀ • rods are surrounded by blebs in interphotoreceptor matrix

short retina rod cell outer segment ( J:120903 )

♀ • at 6 months of age, rod outer segments are severely reduced in superior/inferior and nasal/temporal quadrants

♀ • in retina, rod outer segments are shorter and narrower than in wild-type, and appear banded by alternating regions of dense membrane layers and lumen-containing tubules

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Leber congenital amaurosis 1		DOID:0110078	OMIM:204000	J:120903