Phenotypes associated with this allele

• Allele Symbol: Lrp2^tm1Her
• Allele Name: targeted mutation 1, Joachim Herz
• Allele ID: MGI:1931859
• Summary: 5 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Lrp2^tm1Her/Lrp2^tm1Her	either: (involves: 129S7/SvEvBrd * CD-1) or (involves: 129/SvEmcTer * 129S7/SvEvBrd * C57BL/6N)	MGI:3790971
hm2	Lrp2^tm1Her/Lrp2^tm1Her	involves: 129S7/SvEvBrd	MGI:3790867
hm3	Lrp2^tm1Her/Lrp2^tm1Her	involves: 129S7/SvEvBrd * C57BL/6	MGI:3790950
hm4	Lrp2^tm1Her/Lrp2^tm1Her	involves: 129S7/SvEvBrd * C57BL/6 * FVB/NJ	MGI:5697335
ht5	Lrp2^tm1Her/Lrp2^+	involves: 129S7/SvEvBrd * C57BL/6	MGI:3790951

Genotype
MGI:3790971

hm1

• Allelic Composition: Lrp2^tm1Her/Lrp2^tm1Her
• Genetic Background: either: (involves: 129S7/SvEvBrd * CD-1) or (involves: 129/SvEmcTer * 129S7/SvEvBrd * C57BL/6N)

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

reproductive system

abnormal testis morphology ( J:115189 )

♂ • the cryptorchid testis of the few mutants that survive to adulthood is characterized by degenerated germinal epithelia of the seminiferous tubules and by the absence of germ cells

abnormal testis development ( J:115189 )

♂ • mutants exhibit a failure of cranial suspensory ligament (CSL) regression at E18.5; both the gubernaculums and CSL are still present at the lower and upper pole of the gonads, respectively, with the CSL tethering the testes and epididymi to the abdominal body wall dorsal to the kidney

unilateral cryptorchism ( J:115189 )

♂ • the left testis does not descend into the scrotum and is poorly developed and severely retarded in size in the few males that survive to adulthood

dilated uterus ( J:115189 )

♀ • as a result of the closed vagina cavity, uterine fluid accumulates in the uterus, grossly inflating the organ

vaginal septum ( J:115189 )

♀ • the vagina opening is closed by a septum composed of an epithelial cell layer followed by connective tissue and skin in the few females that survive to adulthood

homeostasis/metabolism

increased circulating dihydrotestosterone level ( J:115189 )

• circulating DHT is increased 2-fold in E14.5 male embryos

increased circulating testosterone level ( J:115189 )

• circulating testosterone is increased 2-fold in E14.5 male embryos

abnormal response/metabolism to endogenous compounds ( J:115189 )

• neither male nor female embryos respond to exogenous androgen or estrogen application, respectively, indicating steroid insensitivity

endocrine/exocrine glands

abnormal testis morphology ( J:115189 )

♂ • the cryptorchid testis of the few mutants that survive to adulthood is characterized by degenerated germinal epithelia of the seminiferous tubules and by the absence of germ cells

abnormal testis development ( J:115189 )

♂ • mutants exhibit a failure of cranial suspensory ligament (CSL) regression at E18.5; both the gubernaculums and CSL are still present at the lower and upper pole of the gonads, respectively, with the CSL tethering the testes and epididymi to the abdominal body wall dorsal to the kidney

unilateral cryptorchism ( J:115189 )

♂ • the left testis does not descend into the scrotum and is poorly developed and severely retarded in size in the few males that survive to adulthood

Genotype
MGI:3790867

hm2

• Allelic Composition: Lrp2^tm1Her/Lrp2^tm1Her
• Genetic Background: involves: 129S7/SvEvBrd

mortality/aging

perinatal lethality, complete penetrance ( J:34835 )

• about 50% die within the first few minutes because of an inability to breathe; the others initially ventilate normally but die from respiratory insufficiency within 2-3 hours

growth/size/body

flat forehead ( J:34835 )

• newborns show a flattened forehead

short snout ( J:34835 )

• nose is shortened in newborns

decreased embryo size ( J:34835 )

• embryos are smaller at E9.5

embryo

decreased embryo size ( J:34835 )

• embryos are smaller at E9.5

abnormal embryonic neuroepithelium morphology ( J:34835 )

• E8.5 embryos exhibit impaired epithelial cohesion resulting in uneven cobblestone-like neuroepithelial surface

delayed neural tube closure ( J:34835 )

• at E9.5, anterior neural tube closure is frequently delayed

nervous system

abnormal embryonic neuroepithelium morphology ( J:34835 )

• E8.5 embryos exhibit impaired epithelial cohesion resulting in uneven cobblestone-like neuroepithelial surface

delayed neural tube closure ( J:34835 )

• at E9.5, anterior neural tube closure is frequently delayed

abnormal forebrain development ( J:34835 )

small embryonic telencephalon ( J:34835 )

• smaller at E9.5

holoprosencephaly ( J:34835 )

• fusion of the forebrain hemispheres

• the lateral (IV) and III ventricles are frequently fused to form a common holoprosencephalic cavity in 6 of 10 mutants

abnormal choroid plexus morphology ( J:34835 )

• mutants often have a characteristic protrusion in the midline of the crown that is caused by a prolapse of the choroid plexus

abnormal telencephalon morphology ( J:34835 )

• small telencephalon with an uneven edge of the neural folds

absent corpus callosum ( J:34835 )

• absent in 9 of 10 mutants

absent olfactory bulb ( J:34835 )

• newborns show an almost invariable absence of the olfactory bulbs

exencephaly ( J:34835 )

• seen in 10 of 106 newborns

respiratory system

atelectasis ( J:34835 )

• newborns exhibit atelectic areas in the lungs

overexpanded pulmonary alveolus ( J:34835 )

abnormal respiratory system physiology ( J:34835 )

emphysema ( J:34835 )

• newborns exhibit emphysematous areas in the lungs

respiratory failure ( J:34835 )

homeostasis/metabolism

cyanosis ( J:34835 )

• about 50% of mutants remain severely cyanotic after birth and die within the first few minutes

abnormal urine homeostasis ( J:108230 )

• urine of the 2% of mutants that survive to adulthood contains increased amounts of vitamin A (retinol) and 25-OH vitamin D3

increased urine protein level ( J:108230 , J:184259 )

• the 2% of mutants that survive to adult hood exhibit renal resorption deficiency as seen by the excretion of low molecular weight plasma proteins in the urine (low molecular weight plasma proteinuria) (J:108230)

• proteins excreted include small plasma proteins that carry lipophilic compounds including vitamin D-binding protein, retinol-binding protein, alpha1-microglobulin and odorant-binding protein, indicating urinary loss of lipophilic vitamins bound to the carrier proteins (J:108230)

• adult survivors excrete vitamin D-binding protein and retinol-binding protein (J:184259)

increased urine microglobulin level ( J:108230 )

• increased urine alpha1-microglobulin level

craniofacial

abnormal viscerocranium morphology ( J:34835 )

• variable degree of frontonasal bone dysmorphology, however rest of the skeleton appears normal

flat forehead ( J:34835 )

• newborns show a flattened forehead

short snout ( J:34835 )

• nose is shortened in newborns

renal/urinary system

abnormal urine homeostasis ( J:108230 )

• urine of the 2% of mutants that survive to adulthood contains increased amounts of vitamin A (retinol) and 25-OH vitamin D3

increased urine protein level ( J:108230 , J:184259 )

• the 2% of mutants that survive to adult hood exhibit renal resorption deficiency as seen by the excretion of low molecular weight plasma proteins in the urine (low molecular weight plasma proteinuria) (J:108230)

• proteins excreted include small plasma proteins that carry lipophilic compounds including vitamin D-binding protein, retinol-binding protein, alpha1-microglobulin and odorant-binding protein, indicating urinary loss of lipophilic vitamins bound to the carrier proteins (J:108230)

• adult survivors excrete vitamin D-binding protein and retinol-binding protein (J:184259)

increased urine microglobulin level ( J:108230 )

• increased urine alpha1-microglobulin level

abnormal proximal convoluted tubule morphology ( J:34835 , J:108230 )

• decrease in the number and size of large endosomes in proximal tubular epithelial cells (reduction in the number of endocytic apical vesicles) (J:34835)

• the 2% of mutants that survive to adulthood exhibit a reduction in the number of coated pits, endosomes, and lysosomes in kidney proximal tubules (J:108230)

skeleton

abnormal viscerocranium morphology ( J:34835 )

• variable degree of frontonasal bone dysmorphology, however rest of the skeleton appears normal

vision/eye

microphthalmia ( J:34835 )

• seen in some mutants

anophthalmia ( J:34835 )

• seen in some mutants

cellular

increased apoptosis ( J:34835 )

• increase in apoptosis is seen at E9.5 in areas that correspond to regions containing facio-acoustic (VII) or trigeminal (V) neural crest, as well as around the optic vesicle

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Fanconi syndrome		DOID:1062	OMIM:PS134600	J:108230

Genotype
MGI:3790950

hm3

• Allelic Composition: Lrp2^tm1Her/Lrp2^tm1Her
• Genetic Background: involves: 129S7/SvEvBrd * C57BL/6

mortality/aging

perinatal lethality, incomplete penetrance ( J:134797 )

• most mutants die shortly after birth, although a few homozygotes reach adulthood

hearing/vestibular/ear

abnormal strial marginal cell morphology ( J:134797 )

• lipofuscin granules are more abundant in the marginal cells than in wild-type

• the number of microvilli in marginal cells of the stria vascularis is reduced

• apical surfaces of marginal cells are more irregular than in wild-type

abnormal hearing physiology ( J:134797 )

increased or absent threshold for auditory brainstem response ( J:134797 )

• the two surviving mutants exhibit increased ABR threshold indicating hearing loss at 3 months of age

increased susceptibility to age-related hearing loss ( J:134797 )

• strial presbycusis

impaired hearing ( J:134797 )

• analysis of ABR thresholds shows that the two surviving mutants exhibit profound hearing loss at 3 months of age

Genotype
MGI:5697335

hm4

• Allelic Composition: Lrp2^tm1Her/Lrp2^tm1Her
• Genetic Background: involves: 129S7/SvEvBrd * C57BL/6 * FVB/NJ

homeostasis/metabolism

abnormal selenium level ( J:211934 , J:211934 )

• on a normal selenium diet kidney selenium levels are around 62% of control levels even though whole body levels are normal (J:211934)

♀ • female mice on a low selenium diet have reduced whole body selenium levels after 12 weeks on the diet, particularly in the kidney (J:211934)

increased urine selenium level ( J:211934 )

• seleno proteins found in the urine, unlike controls

• selenium primarily on N-terminal Sepp1 fragments

decreased glutathione peroxidase activity ( J:211934 )

• plasma activity about 32% of control activity on a normal selenium diet

growth/size/body

growth/size/body region phenotype ( J:211934 )

N • normal body weight

behavior/neurological

behavior/neurological phenotype ( J:211934 )

N • normal neurological phenotypes but not tested thoroughly

renal/urinary system

increased urine selenium level ( J:211934 )

• seleno proteins found in the urine, unlike controls

• selenium primarily on N-terminal Sepp1 fragments

Genotype
MGI:3790951

ht5

• Allelic Composition: Lrp2^tm1Her/Lrp2⁺
• Genetic Background: involves: 129S7/SvEvBrd * C57BL/6

hearing/vestibular/ear

abnormal ear physiology ( J:134797 )

• uptake of FITC-labeled beta-estrogen into the strial marginal cells is reduced

increased or absent threshold for auditory brainstem response ( J:134797 )

• heterozygotes older than 6 months exhibit a moderate, but significant, elevation in click-ABR threshold

impaired hearing ( J:134797 )

• moderate hearing loss is seen at 6 months of age