Phenotypes associated with this allele

• Allele Symbol: Lrp2^tm1Tew
• Allele Name: targeted mutation 1, Thomas E Willnow
• Allele ID: MGI:2449765
• Summary: 7 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Lrp2^tm1Tew/Lrp2^tm1Tew	Not Specified	MGI:2667816
cn2	Foxg1^tm1(cre)Skm/Foxg1^+ Lrp2^tm1Tew/Lrp2^tm1Tew	involves: 129P2/OlaHsd	MGI:6199478
cn3	Lrp2^tm1Tew/Lrp2^tm1Tew Meox2^tm1(cre)Sor/Meox2^+	involves: 129S4/SvJaeSor	MGI:4831006
cn4	Cubn^tm1Rkoz/Cubn^tm1Rkoz Lrp2^tm1Tew/Lrp2^tm1Tew Meox2^tm1(cre)Sor/Meox2^+	involves: 129S4/SvJaeSor * 129X1/SvJ * C57BL/6	MGI:4831007
cn5	H2az2^Tg(Wnt1-cre)11Rth/H2az2^+ Lrp2^tm1Tew/Lrp2^tm1Tew	involves: C57BL/6J * CBA/J	MGI:6199475
cn6	Lrp2^tm1Tew/Lrp2^tm1Tew Tg(GFAP-cre)25Mes/0	involves: FVB/N	MGI:6199477
cn7	Lrp2^tm1Tew/Lrp2^tm1Tew Tg(APOE-cre)VITew/0	Not Specified	MGI:2667817

Genotype
MGI:2667816

hm1

• Allelic Composition: Lrp2^tm1Tew/Lrp2^tm1Tew
• Genetic Background: Not Specified

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

skeleton

decreased bone mineral content ( J:81496 )

• on a vitamin D-depleted diet, homozygotes display only a slight reduction in total bone mineral content relative to control mice

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:81496 )

N • homozygotes display normal urine samples relative to wild-type littermates

nervous system

nervous system phenotype ( J:81496 )

N • homozygotes exhibit normal forebrain development

Genotype
MGI:6199478

cn2

• Allelic Composition: Foxg1^tm1(cre)Skm/Foxg1⁺; Lrp2^tm1Tew/Lrp2^tm1Tew
• Genetic Background: involves: 129P2/OlaHsd

vision/eye

increased retina apoptosis ( J:238249 )

• increase in cell death in the retina between P5 and P21 and cell death increases, especially in the ganglion cell layer, with age

abnormal eye morphology ( J:238249 )

• the retrobulbar space (the space between the eyeball and the orbit) is reduced

• excessive axial elongation and posterior pole degenerative changes in eyes

• chorioretinal atrophy in some cases

• myopic chorioretinopathy

abnormal placement of pupils ( J:238249 )

• anterior segment is generally normal although pupillary ectopia is occasionally seen

abnormal lens morphology ( J:238249 )

• the lens thickness increases during postnatal development as in wild-type eyes but is lower at P330 and P390

ocular hypotelorism ( J:238249 )

• shorter inter-ocular distance

macrophthalmia ( J:238249 )

• bilateral eye enlargement

• eyes are 30% and 40% longer at P60 and P180

abnormal posterior eye segment morphology ( J:238249 )

• posterior staphyloma is seen from P21 onward

• lengthening of the ocular axis is primarily due to continuous vitreal chamber enlargement

• the vitreous chamber depth of eyes increases dramatically at all ages studied

• however, the anterior chamber depth and corneal radius of curvature increases similarly to wild-type from P15 to P510

decreased retina ganglion cell number ( J:238249 )

• cell density in the ganglion cell layer is first decreased at P15

abnormal retina bipolar cell morphology ( J:238249 )

• bipolar cells exhibit atrophic dendrites and their connections with the retinal ganglion cells appear thicker

abnormal optic nerve morphology ( J:238249 )

• reduction in the number of axons in the optic nerve at P150

• the optic nerve diameter is slightly increased at P150

abnormal retina pigment epithelium morphology ( J:238249 )

• peripapillary atrophy of the pigment epithelium consistent with a peripapillary staphyloma, a trait of myopic retinopathy

abnormal retina pigmentation ( J:238249 )

• widespread pigment dispersion affects most of the retina

thin retina inner nuclear layer ( J:238249 )

• thickness of the inner nuclear layer is decreased more than in wild-type mice from P5 to P90

• progressive decrease in cell density in the inner nuclear from P5 onwards

thin retina inner plexiform layer ( J:238249 )

• significant reduction of the inner plexiform layer thickness from P7 onwards

thin retina outer nuclear layer ( J:238249 )

• thickness of the outer nuclear layer is decreased more than in wild-type mice from P5 to P90

• progressive decrease in cell density in the outer nuclear layer from P5 onwards

decreased total retina thickness ( J:238249 )

• retinal thinning from P15 onwards

abnormal sclera morphology ( J:238249 )

• collagen fibrils in sclera form fewer lamellae at P90 and P180 and appear disorganized

• within lamellae, the organization of collagen fibrils is perturbed, with fibrils coursing parallel to each other and large areas devoid of fibrils rather than interweaving as in controls

• collagen fibril density is lower in the sclera

• morphology of collagen fibrils is very heterogeneous and their contour is irregular with rectangular- rather than oval-shaped fibrils, mean cross-sectional diameter is increased and the frequency of collagen fibers with both smaller and wider mean cross-sectional diameter is increased, indicating scleral staphyloma

sclera thinning ( J:238249 )

• scleral thickness at P90 and P180 is thinner by 33% and 50%, respectively

abnormal intraocular pressure ( J:238249 )

• intraocular pressure is lower at P330 and P390 but normal at other times

high myopia ( J:238249 )

cellular

increased retina apoptosis ( J:238249 )

• increase in cell death in the retina between P5 and P21 and cell death increases, especially in the ganglion cell layer, with age

decreased cell proliferation ( J:238249 )

• reduction of the proliferation index is seen at P3 and P5 in the eyes

nervous system

absent corpus callosum ( J:238249 )

abnormal dendrite morphology ( J:238249 )

• bipolar cells exhibit atrophic dendrites

decreased retina ganglion cell number ( J:238249 )

• cell density in the ganglion cell layer is first decreased at P15

abnormal retina bipolar cell morphology ( J:238249 )

• bipolar cells exhibit atrophic dendrites and their connections with the retinal ganglion cells appear thicker

abnormal optic nerve morphology ( J:238249 )

• reduction in the number of axons in the optic nerve at P150

• the optic nerve diameter is slightly increased at P150

pigmentation

abnormal retina pigment epithelium morphology ( J:238249 )

• peripapillary atrophy of the pigment epithelium consistent with a peripapillary staphyloma, a trait of myopic retinopathy

abnormal retina pigmentation ( J:238249 )

• widespread pigment dispersion affects most of the retina

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
degenerative myopia		DOID:11829		J:238249

Genotype
MGI:4831006

cn3

• Allelic Composition: Lrp2^tm1Tew/Lrp2^tm1Tew; Meox2^tm1(cre)Sor/Meox2⁺
• Genetic Background: involves: 129S4/SvJaeSor

renal/urinary system

abnormal renal reabsorption ( J:164025 )

• mice exhibit reduced uptake of intrinsic factor vitamin B12 complex and apoA-I by proximal tubule cells

Genotype
MGI:4831007

cn4

• Allelic Composition: Cubn^tm1Rkoz/Cubn^tm1Rkoz; Lrp2^tm1Tew/Lrp2^tm1Tew; Meox2^tm1(cre)Sor/Meox2⁺
• Genetic Background: involves: 129S4/SvJaeSor * 129X1/SvJ * C57BL/6

mortality/aging

neonatal lethality, incomplete penetrance ( J:164025 )

• most die shortly after birth, however a few mice live to adulthood

homeostasis/metabolism

albuminuria ( J:164025 )

• mice exhibit albuminuria to the same extent as conditional homozygous Cubn mice

renal/urinary system

albuminuria ( J:164025 )

• mice exhibit albuminuria to the same extent as conditional homozygous Cubn mice

abnormal kidney morphology ( J:164025 )

• renal morphology is similar to that in single homozygous Lrp2 mice

abnormal renal reabsorption ( J:164025 )

• absence of uptake of apoA-I by proximal tubule cells

Genotype
MGI:6199475

cn5

• Allelic Composition: H2az2^{Tg(Wnt1-cre)11Rth}/H2az2⁺; Lrp2^tm1Tew/Lrp2^tm1Tew
• Genetic Background: involves: C57BL/6J * CBA/J

vision/eye

vision/eye phenotype ( J:238249 )

N • mice exhibit normal retinal differentiation and eye formation

Genotype
MGI:6199477

cn6

• Allelic Composition: Lrp2^tm1Tew/Lrp2^tm1Tew; Tg(GFAP-cre)25Mes/0
• Genetic Background: involves: FVB/N

vision/eye

vision/eye phenotype ( J:238249 )

N • mice exhibit normal retinal differentiation and eye formation

Genotype
MGI:2667817

cn7

• Allelic Composition: Lrp2^tm1Tew/Lrp2^tm1Tew; Tg(APOE-cre)VITew/0
• Genetic Background: Not Specified

homeostasis/metabolism

increased circulating parathyroid hormone level ( J:81496 )

• on a vitamin D-depleted diet, mutant mice exhibit an appropriate increase in circulating PTH levels in reponse to hypocalcemia

decreased circulating calcium level ( J:81496 )

• on a vitamin D-depleted diet, mutant mice exhibit hypocalcemia due to hypovitaminosis D

abnormal vitamin D level ( J:81496 )

• on a normal (vitamin D-repleted) diet, urinary loss of 25-OH vitamin D₃ coincides with a 50% reduction in the plasma levels of 25-OH vitamin D₃ and of 1,25-(OH)₂ D₃ while serum calcium, phosphorus, and PTH levels remain unchanged relative to homozygous Lrp2^tm1Tew control mice

• on a vitamin D-depleted diet, the plasma levels of 25-OH vitamin D₃ and of 1,25-(OH)₂ D₃ are reduced to the lowest detection levels along with a marked reduction in serum calcium levels and an increase in PTH levels

abnormal urine homeostasis ( J:81496 )

• a 5- to 6-fold increase in urinary excretion of ¹²⁵I-labeled vitamin D-binding protein (DBP) and ³H-25-OH vitamin D₃ is observed relative to homozygous Lrp2^tm1Tew control mice

increased urine protein level ( J:81496 )

• mutant kidneys display impaired retrieval of plasma proteins from the glomerular filtrate and excrete increased amounts of low molecular weight proteins into the urine, including vitamin D-binding protein (DBP) and retinol-binding protein (RBP)

skeleton

decreased bone mineral content ( J:81496 )

• the total bone mineral content in femur and tibia is drastically decreased relative to control mice

abnormal bone mineralization ( J:81496 )

• on a vitamin D-deficient chow, mutant verebrates exhibit a highly abnormal and unmineralized bone surface that is mostly covered by osteoid (uncalcified matrix)

• a significant increase in osteoid surface, osteoid width, and osteoid volume and a concomittant reduction in the mineralizing bone surfaces are observed

osteomalacia ( J:81496 )

• after 6 weeks on a vitamin D-deficient chow, mutant mice exhibit true severe osteomalacia (softening of the bones) as a result of hypovitaminosis D

• osteopathy is characterized by a reduction in bone mineral content, an increase in osteoid surfaces, and a lack of mineralizing activity

abnormal bone remodeling ( J:81496 )

• on a normal diet, mutant lumbar vertebral bodies show a moderate but consistent increase in resorptive cavities and osteoid-covered surfaces, indicating increased resorption and remodeling activity

increased bone resorption ( J:81496 )

• a modest increase in resorptive surface area is observed, as 67% of osteoid surfaces block access of osteoclasts to the bones

renal/urinary system

abnormal urine homeostasis ( J:81496 )

• a 5- to 6-fold increase in urinary excretion of ¹²⁵I-labeled vitamin D-binding protein (DBP) and ³H-25-OH vitamin D₃ is observed relative to homozygous Lrp2^tm1Tew control mice

increased urine protein level ( J:81496 )

• mutant kidneys display impaired retrieval of plasma proteins from the glomerular filtrate and excrete increased amounts of low molecular weight proteins into the urine, including vitamin D-binding protein (DBP) and retinol-binding protein (RBP)