Mouse Genome Informatics
ht
    Bmp4tm1Blh/Bmp4+
B6.129S2-Bmp4tm1Blh/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       

Anterior eye segment abnormalities in Bmp4tm1Blh/Bmp4+ mice

mortality/aging
• less than half as many heterozygotes are born as expected

vision/eye
• Background Sensitivity: mutants on a C57BL/6J background exhibit variable anterior and posterior segment abnormalities that are reduced on a mixed C3Hf/HeA and C57BL/LiA background and are rarely seen in mutants on CAST/Ei, 129S6/SvEvTac, or BALB/cJ background
• variable anterior segment abnormalities in mutants 3-5 months of age
• abnormal in most eyes
• small or absent
• displaced Schwalbe's line
• hypoplastic or absent trabecular meshwork that appears compressed and stalled in development
• hypoplastic or absent trabecular meshwork that appears compressed and stalled in development
• pupils are often eccentrically located
• iris is generally normal, however in some eyes, the iris is hypoplastic and malformed; occasionally the malformation is extensive involving both iris and ciliary body
• extracellular matrix (ECM) abnormalities are seen in the peripheral cornea, showing irregularly arranged collagen bundles
• abnormal iridocorneal attachments (anterior synechiae) of variable extent
• peripheral cornea is often thinner with neovascularization
• some eyes exhibit scleralization (opacity) of the the peripheral cornea or diffuse corneal haze
• anterior subcapsular and cortical contaracts occur in most mutants
• anterior subcapsular and cortical contaracts occur in most mutants
• frequency increased 3 fold
• variable posterior eye segment abnormalities
• abnormalities of the optic nerve head are frequently observed
• optic nerve abnormalities range from normal to absent, and are most often severely abnormal consisting of loose connective tissue, with absence of neural tissue
• the optic nerve is sometimes absent
• the main retinal vessels branch close to the optic nerve and are irregularly arranged compared to wild-type
• retinal ganglion cell layer on average contains about 50% the normal number of cells
• photoreceptor layer typically appears normal, however there are foci of retinal dysplasia, characterized by rosette formation
• about 25% of heterozygotes exhibit retinal detachment as early as P30, with increased incidence as mice age
• dense network of small tortuous vessels throughout the vitreous that leak fluorescein, indicating compromised integrity of the vessels
• abnormal persistence of the anterior hyaloid vessels
• posterior hyaloid vessels persist throughout the 17 month period studied and increase in number and size beyond that normally seen at birth
• irregular white patches in the vitreous and dense vitreous haze in the majority of eyes
• frequency increased 3 fold
• in some eyes, both a- and b-wave amplitude are reduced, due in part to poor pupillary dilation, with preferential loss of b-wave relative to a-wave
• mutants with severe drainage structure abnormalities over 80% or more of their angle's extent have elevated intraocular pressure

hearing/vestibular/ear
• circling heterozygotes display low gain ratios with yaw axis rotation in the vestibulo-collic reflex, indicating poorer head stability relative to wild-type mice; poor response is consistent with horizontal semicircular canal dysfunction
• in the pitch axis, circling heterozygotes display as good or better head stability than wild-type mice, with gain ratios being greater or equal to 1
• in contrast, non-circling heterozygotes have gain ratios of greater or equal to 1 in both the yaw and pitch axes, indicating normal VCR function
• 2 of 4 circler and 2 of 4 non-circler heterozygotes show reduced neuronal processes in the organ of Corti
• in contrast, the saccule, utricle and ampullae of heterozygotes show normal numbers of neuronal processes
• 4 of 6 circling heterozygotes display a significantly reduced number of stereocilia in their ampullae relative to wild-type; the other two circlers show a patchy decrease in the number of stereocilia
• in contrast, circling heterozygotes show normal stereocilia in the organ of Corti, saccule and utricle
• non-circling heterozygotes have normal-appearing stereocilia in both auditory and vestibular tissues
• most circling heterozygotes exhibit elevated ABR thresholds across all test frequencies (7 out of 11 mice at 6 kHz and 12 kHz; 8 out of 11 mice at 24 kHz)
• non-circlers display elevated ABR thresholds similar to those of circlers
• both circling and non-circling heterozygotes display a partial hearing loss, as assessed by ABR testing

nervous system
• 4 of 6 circling heterozygotes display a significantly reduced number of stereocilia in their ampullae relative to wild-type; the other two circlers show a patchy decrease in the number of stereocilia
• in contrast, circling heterozygotes show normal stereocilia in the organ of Corti, saccule and utricle
• non-circling heterozygotes have normal-appearing stereocilia in both auditory and vestibular tissues
• neuronal processes innervating the cochlea of both circling and non-circling heterozygotes mice are reduced in number
• abnormalities of the optic nerve head are frequently observed
• optic nerve abnormalities range from normal to absent, and are most often severely abnormal consisting of loose connective tissue, with absence of neural tissue
• the optic nerve is sometimes absent

behavior/neurological
• circling heterozygotes display low gain ratios with yaw axis rotation in the vestibulo-collic reflex, indicating poorer head stability relative to wild-type mice; poor response is consistent with horizontal semicircular canal dysfunction
• in the pitch axis, circling heterozygotes display as good or better head stability than wild-type mice, with gain ratios being greater or equal to 1
• in contrast, non-circling heterozygotes have gain ratios of greater or equal to 1 in both the yaw and pitch axes, indicating normal VCR function
• by 2 weeks of age, 10% of heterozygous pups display circling behavior
• 1 of 2 circlers spent 50% of the time circling in a clockwise direction, 17% in a counterclockwise direction and 33% not circling
• the second circler spent 65% of the time circling in a clockwise direction, 1% in a counterclockwise direction and 34% not circling

reproductive system
• sometimes cystic (J:42445)
• sometimes with abnormal lobulation (J:42445)
• sometimes cystic (J:42445)
• female heterozygotes are poorer breeders relative to wild-type females (J:118380)
• average litter from mating a wild-type C57BL/6 mouse with a C57BL/6 heterozygote yields only 1 heterozygous pup

cardiovascular system
• the main retinal vessels branch close to the optic nerve and are irregularly arranged compared to wild-type

renal/urinary system
• marked hydronephrosis in 12% of heterozygotes but ureter is undilated
• cortex of remaining kidney is atrophic
• single cystic kidney in about 12% of heterozygotes
• multiple cysts involving both tubules and glomeruli
• single cystic kidney in about 12% of heterozygotes

craniofacial
• in about 12% of individuals
• in about 12% of individuals

limbs/digits/tail
• 12% with unilateral anterior polydactyly involving the right hind limb only

skeleton
• in about 12% of individuals
• in about 12% of individuals

endocrine/exocrine glands
• sometimes cystic (J:42445)
• sometimes with abnormal lobulation (J:42445)
• sometimes cystic (J:42445)

Mouse Models of Human Disease
OMIM IDRef(s)
Axenfeld-Rieger Syndrome, Type 3; RIEG3 602482 J:82877