Overview

Also Known As:Col4a5 KI

These targeted knock-in mice develop kidney abnormalities, die prematurely, and serve as a model of human X-linked Alport syndrome.

Donating Investigator

Yoav Segal, University of Minnesota

Genetic overview

Genetic Background	Generation

Col4a5^tm1Yseg

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout, Inserted expressed sequence, Humanized sequence)	Col4a5	collagen, type IV, alpha 5

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Research Applications

Mouse/Human Gene Homologs
Endocrine Deficiency Research
Internal/Organ Research
Research Tools

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

Heterozygous females and hemizygous males for the targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. Immunofluorescence analysis of kidney tissue from mutant male mice does not detect gene product (protein), but in kidney from mutant female mice a mosaic pattern of gene product (protein) is detected (due to X-inactivation). RNase protection assay analysis of kidney tissue from mutant male mice detects a significantly lower level than wildtype. Hemizygous male and heterozygous female mice develop progressive kidney disease. By 7 weeks of age, 97% of mutant male mice and 78% of heterozygous female mice exhibit proteinuria. Histological analysis of kidneys from mutant male mice at 4 weeks of age reveals thickened capillary walls and mesangial hypercellularity. The pathology progresses to interstitial inflammation, glomerular abnormalities, and focal sclerosis. Electron microscopic examination of glomerular basement membrane ultrastructure shows lamellation and splitting abnormalities. Female mice heterozygous for the mutation exhibit similar progressive kidney disease but at later onset. These mice do not contain the neo selection cassette. This mutant mouse strain may be useful in studies of X-linked Alport syndrome (XLAS).

Development

A targeting vector containing a loxP site flanked neomycin resistance gene and a point mutation was used to insert a G213T transversion into exon 1. The construct was electroporated into 129SvJ derived ESVJ-1182 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric animals were crossed to FVB/N-Tg(ACTB-cre) 2Mrt/J (JAX STOCK#3376) mice to remove the neo selection cassette and then backcrossed to C57BL/6 for 15 generations.

Control Suggestions

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Genetics

Col4a5^tm1Yseg

Allele Symbol: Col4a5^tm1Yseg

Allele Name	targeted mutation 1, Yoav Segal
Allele Type	Targeted (Null/Knockout, Inserted expressed sequence, Humanized sequence)
Allele Synonym(s)	COL4A5^-
Gene Symbol and Name	Col4a5, collagen, type IV, alpha 5
Gene Synonym(s)
Promoter	Col4a5, collagen, type IV, alpha 5, mouse, laboratory
Strain of Origin	129X1/SvJ
Chromosome	X
Molecular Note	A targeting construct was designed to insert a G to T nucleotide transversion into exon 1. This mutation converts codon 5 from a glycine to a stop codon (G5X). Expression of the alpha5(IV) chain was lost in mutant kidneys from males. Basement membrane expression of the alpha 3(IV) chain was lost as well as that of the alpha6(IV) chain. Expression of alpha1(IV) and alpha2(IV) was conserved. Expression of the alpha5(IV) and alpha3(IV) chains in kidneys from females was mosaic, reflecting X-inactivation.
Mutations Made By	Yoav Segal, University of Minnesota

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

X-linked Alport syndrome

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Mouse/Human Gene Homologs
- Alport syndrome
Endocrine Deficiency Research
- Kidney Defects
Internal/Organ Research
- Kidney Defects
Research Tools
- Internal/Organ Research

Mammalian Phenotype Terms by Genotype

The following phenotype relates to a compound genotype created using this strain

Genotype: Col4a5^tm1Yseg/Col4a5⁺
B6.Cg-Col4a5

homeostasis/metabolism phenotype

increased blood urea nitrogen level

increased urine protein level
- urine concentrations of protein greater than 10 mg/mg creatinine are seen in 78% of females after 9 weeks of age

vision/eye phenotype

abnormal eye physiology
- lenses strain significantly more than wild-type lenses in the anterior-posterior direction (along their thickness but not in the equatorial direction) in osmotic swelling experiments indicating increased distensibility of lens capsule

abnormal lens capsule morphology
- lenses strain significantly more than wild-type lenses in the anterior-posterior direction (along their thickness but not in the equatorial direction) in osmotic swelling experiments indicating increased distensibility of lens capsule

mortality/aging

premature death
- females become ill and begin to die at 8 weeks of age with a median survival age of 39 weeks; however, some survive to 50 weeks of age

renal/urinary system phenotype

abnormal kidney morphology
- in older, visibly ill mice, kidneys appear pale and dull and are pockmarked
- the appearance of kidney abnormalities is delayed relative to hemizygous mutant males

abnormal renal glomerulus morphology
- abnormalities similar to those in males are seen but at later times
- at 17 weeks of age some glomeruli develop focal areas of lamellation and other diffuse changes with widespread abnormalities seen at 30 weeks of age

abnormal renal tubule morphology
- abnormalities similar to those in males are seen but at later times

increased urine protein level
- urine concentrations of protein greater than 10 mg/mg creatinine are seen in 78% of females after 9 weeks of age

pale kidney
- in older, visibly ill mice, kidneys appear pale

Genotype: Col4a5^tm1Yseg/Y
B6.Cg-Col4a5

cardiovascular system phenotype

abnormal glomerular capillary morphology
- at 4 weeks of age capillary wall thickening is seen
- capillary loop dilation, simplification, and capillary tuft collapse may be seen at 17 weeks of age

dilated glomerular capillary
- capillary loop dilation may be seen at 17 weeks of age

vision/eye phenotype

abnormal eye physiology
- lenses strain significantly more than wild-type lenses in the anterior-posterior direction (along their thickness but not in the equatorial direction) in osmotic swelling experiments indicating increased distensibility of lens capsule

abnormal lens capsule morphology
- lenses strain significantly more than wild-type lenses in the anterior-posterior direction (along their thickness but not in the equatorial direction) in osmotic swelling experiments indicating increased distensibility of lens capsule

homeostasis/metabolism phenotype

increased blood urea nitrogen level

increased urine protein level
- urine concentrations of protein greater than 10 mg/mg creatinine are seen in 97% of males after 7 weeks of age

immune system phenotype

tubulointerstitial nephritis
- at 17 weeks of age widespread interstitial inflammation is seen

mortality/aging

premature death
- males become ill and begin to die at 6 weeks of age with none surviving beyond 34 weeks of age
- median survival is 23 weeks of age

renal/urinary system phenotype

abnormal glomerular capillary morphology
- at 4 weeks of age capillary wall thickening is seen
- capillary loop dilation, simplification, and capillary tuft collapse may be seen at 17 weeks of age

abnormal kidney morphology
- in older, visibly ill mice, kidneys appear pale and dull and are pockmarked

abnormal renal glomerulus basement membrane morphology
- at 4 weeks of age lamellation of glomerular basement membranes is present
- by 17 weeks of age diffuse basement membrane abnormalities including lamellation and splitting are seen

abnormal renal glomerulus morphology
- at 17 weeks of age glomeruli display many, variable abnormalities including capillary loop dilation and simplification, capillary tuft collapse, capsular adhesions, and focal sclerosis

dilated glomerular capillary
- capillary loop dilation may be seen at 17 weeks of age

dilated renal tubules
- at 17 weeks of age tubular dilation is seen

glomerulosclerosis
- focal sclerosis may be observed at at 17 weeks of age

increased urine protein level
- urine concentrations of protein greater than 10 mg/mg creatinine are seen in 97% of males after 7 weeks of age

mesangial cell hyperplasia
- at 4 weeks of age mesangial hypercellularity is seen; however, the tubulointerstitium is similar to wild-type

pale kidney
- in older, visibly ill mice, kidneys appear pale

podocyte foot process effacement
- at 17 weeks of age signs of podocyte injury, including foot process effacement, vesiculation, and denudation, are present

renal glomerular synechia
- at 17 weeks of age capsular adhesions may be seen

renal tubule atrophy
- at 17 weeks of age tubular atrophy is seen

tubulointerstitial nephritis
- at 17 weeks of age widespread interstitial inflammation is seen

References

Additional - Col4a5^tm1Yseg related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Probe:Ptprc End Point-Alternate 1

Breeding Considerations

When maintaining a live colony, homozygous females may be bred to hemizygous males.

Additional Breeding and Husbandry Support

Citation
When using the Col4a5 KI mouse strain in a publication, please cite the originating article(s) and include JAX stock #006183 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

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International

Live Mouse

Age Genotype Price

weeks

Cryorecovery - Pricing

Service/Product Description Price

X linked - Heterozygous females and wildtype males for Col4a5<tm1Yseg>

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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Also Known As:Col4a5 KI

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Col4a5tm1Yseg

Allele Symbol: Col4a5tm1Yseg

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Mammalian Phenotype Terms by Genotype

Genotype: Col4a5tm1Yseg/Col4a5+B6.Cg-Col4a5

homeostasis/metabolism phenotype

vision/eye phenotype

mortality/aging

renal/urinary system phenotype

Genotype: Col4a5tm1Yseg/YB6.Cg-Col4a5

cardiovascular system phenotype

vision/eye phenotype

homeostasis/metabolism phenotype

immune system phenotype

mortality/aging

renal/urinary system phenotype

References

Additional - Col4a5tm1Yseg related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Col4a5^tm1Yseg

Allele Symbol: Col4a5^tm1Yseg

Genotype: Col4a5^tm1Yseg/Col4a5⁺
B6.Cg-Col4a5

Genotype: Col4a5^tm1Yseg/Y
B6.Cg-Col4a5

Additional - Col4a5^tm1Yseg related