Overview

Also Known As:ΔF

These Cftr knock-out mice exhibit neonatal lethality with abnormal bowel development. They may be useful in applications related to the study of cystic fibrosis.

Donating Investigator

Dr. Kirk R. Thomas, Univ of Utah

Genetic overview

Genetic Background	Generation

Cftr^tm1Kth

Allele Type	Gene Symbol	Gene Name
Targeted (Hypomorph)	Cftr	cystic fibrosis transmembrane conductance regulator

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Research Applications

Immunology, Inflammation and Autoimmunity Research
Metabolism Research
Mouse/Human Gene Homologs

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

The Cftr^tm1Kth targeted mutation corresponds to the delta 508 mutation in humans. Homozygous mutant mice show an increased mortality within the first month after birth, with ~60% mortality by post-weaning. Those that survive are fertile, but females are poor breeders. Mutant mice are also reduced in size compared to normal wildtype mice. Those that do not survive to adulthood show bowel obstructions, bowel strictures and peritonitis. Lungs, pancreas, gall bladder, male reproductive tract, lacrimal gland, and submandibular glands from homozygous mice appear normal regardless of the survival of the animal. Homozygous mice also show a tissue-specific loss of CFTR transcripts in the intestine.

Development

The Cftr^tm1Kth targeted mutation was made in the laboratory of Dr. Kirk R. Thomas at the University of Utah. The mutated allele contains a 3-bp (CTT) deletion between bases 1656 and 1660 resulting in the loss of a phenylalanine residue in exon 10 at a position which corresponds to human position 508. The 129S6/SvEv-derived CC1.2 ES cell line was used.

Control Suggestions

Wild-type from the colony
000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Zeiher BG; Eichwald E; Zabner J; Smith JJ; Puga AP; McCray PB Jr; Capecchi MR; Welsh MJ; Thomas KR. 1995. A mouse model for the delta F508 allele of cystic fibrosis. J Clin Invest 96(4):2051-64PubMed: 7560099 MGI: J:29074

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Genetics

Cftr^tm1Kth

Allele Symbol: Cftr^tm1Kth

Allele Name	targeted mutation 1, Kirk R Thomas
Allele Type	Targeted (Hypomorph)
Allele Synonym(s)	c.1656_1660del; CFTRdeltaF508; deltaF; deltaF508 Cftr; p.F508del
Gene Symbol and Name	Cftr, cystic fibrosis transmembrane conductance regulator
Gene Synonym(s)
Promoter	Cftr, cystic fibrosis transmembrane conductance regulator, mouse, laboratory
Strain of Origin	129S7/SvEvBrd
Chromosome	6
General Note	This (J:29074) and other (J:27734, J:28979) targeted mutations reproduce the common human mutation, eliminating the same phenylalanine from the protein sequence. In at least one of these models, the mutant is temperature sensitive, and can be expressed on the apical membrane when cultured at low temperatures, which is also true of the human mutant lacking the same phenylalanine residue (J:35364).
Molecular Note	The allele contains a 3 bp deletion in exon 11 resulting in the loss of phenylalanine codon 508 (p.F508del). This deletion mimics the deltaF508 mutation found in human cystic fibrosis patients. A neomycin selection cassette was also inserted in intron 11 in reverse transcriptional orientation to the gene. In salivary glands transcription levels from the allele are comparable to wild-type, but no protein was detected. Protein was detected in testes but it was mislocalized. Transcription levels in intestine were greatly reduced.
Mutations Made By	Dr. Kirk Thomas, Univ of Utah

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).

cystic fibrosis

Research Areas By Phenotype

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

Immunology, Inflammation and Autoimmunity Research
- Cystic Fibrosis

Genotype: Cftr^tm1Kth related

Metabolism Research
Mouse/Human Gene Homologs
- cystic fibrosis
Immunology, Inflammation and Autoimmunity Research
- Inflammation
  - Inflammatory bowel disease

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Cftr^tm1Kth/Cftr^tm1Kth
involves: 129S7/SvEvBrd * C57BL/6J

growth/size/body region phenotype

decreased body weight
- by weaning, weight was only 50-60% that of controls and although homozygous mutant mice continued to grow, they never reached the size of controls

decreased body size
- reduced size noticeable as early as 10 days after birth

homeostasis/metabolism phenotype

abnormal ion homeostasis
- defective electrolyte transport in nasal, intestinal, and pancreatic duct epithelia

abnormal fluid regulation
- defective fluid transport in nasal, intestinal, and pancreatic duct epithelia

immune system phenotype

peritoneal inflammation
- mice that died prematurely showed peritonitis

mortality/aging

postnatal lethality, incomplete penetrance
- about 10% died within 7 days of birth and saw significant mortality around the time of weaning (30 days after birth), with 40% surviving postweaning for at least 8 months

digestive/alimentary phenotype

abnormal jejunum morphology
- some mice exhibited large casts of mucus material in the jejunum, however lung, pancreas, gall bladder, male reproductive tract, lacrimal gland, and submandibular glands appeared normal

peritoneal inflammation
- mice that died prematurely showed peritonitis

abnormal digestive system physiology
- lacked cAMP-stimulated Cl^- secretory current in intestine, indicating defective electrolyte transport

abnormal intestine morphology
- mice that died prematurely showed evidence of bowel obstruction and bowel strictures, especially in the cecum

intestinal obstruction
- mice that died prematurely showed evidence of bowel obstruction

dilated Brunner's glands
- Brunner's glands were often dilated

endocrine/exocrine gland phenotype

abnormal pancreas physiology
- reduced absorption of fluid and lower cAMP-stimulated fluid secretion by pancreatic epithelia

dilated Brunner's glands
- Brunner's glands were often dilated

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

Genotype: Cftr^tm1Kth/Cftr^tm1Kth
B6.129S7-Cftr

digestive/alimentary phenotype

intestinal obstruction
- develop intestinal blockage when fed a normal (solid) diet

mammalian phenotype

homeostasis/metabolism phenotype
- Normal - although mutant FSH levels are slightly increased relative to wild-type levels, circulating levels of both FSH and LH still remain within normal range at proestrus

mortality/aging

increased susceptibility to bacterial infection induced morbidity/mortality
- reduced ability to respond to lung infection elicited with Pseudomonas aeruginosa- laden agarose beads

reproductive system phenotype

abnormal sperm physiology
- sperm transport within the mutant female reproductive system is significantly impaired: the average number of sperm found in mutant oviducts is only ~10% that of wild-type
- Normal - however, no differences in capacitation of oviductal sperm from mutant and wild-type females are observed

decreased uterus weight
- Normal - however, mutant uterus weight is restored to wild-type values after superovulation
- at 6-8 and 14-16 weeks of age, the average weight of mutant uteri is reduced by 56% and 36%, respectively, relative to that of wild-type uteri

impaired fertilization
- at 48 hrs after hCG treatment, 98.4% of mutant oocytes remain unfertilized, whereas the majority of embryos from superovulated wild-type females are found at the 2- to 4-cell stages
- however, no significant differences in in vitro fertilization rates are observed, suggesting that decreased in vivo fertilization is more likely due to inadequate fluid control in the reproductive tract, resulting in decreased sperm number in the oviduct

absent estrous cycle
- unlike wild-type females, 22.2% of 14-16-wk-old mutant females never enter estrus but are constantly in diestrus

reduced female fertility
- following induction of superovulation, only 1 of 10 mutant females that displayed vaginal plugs gave birth, but that female did give birth to 20 pups
- 35.7% of female homozygotes are unable to give birth over a 5-month mating period
- female homozygotes exhibit reduced fertility with significantly fewer numbers of litters and smaller litter sizes relative to wild-type females

decreased corpora lutea number
- female homozygotes show an average of 1.5 +/- 2.0 corpora lutea per ovary vs 9.3 +/- 1.4 in wild-type females, even though other follicle stages are present

decreased ovary weight
- at 6-8 and 14-16 weeks of age, the average weight of mutant ovaries is reduced by 50% and 36%, respectively, relative to that of wild-type ovaries
- Normal - however, mutant ovarian weight is restored to wild-type values after superovulation

decreased ovulation rate
- Normal - however, normal ovulation rates are observed after induction of superovulation with exogenous hormone (PMSG + hCG) injections
- female homozygotes display reduced oocyte ovulation rates relative to wild-type females

small uterus
- at 7 weeks of age, female homozygotes display smaller uteri than wild-type females

small ovary
- at 7 weeks of age, female homozygotes display smaller ovaries than wild-type females

decreased litter size
- female homozygotes show a significant decrease in average number of pups per litter relative to wild-type females (3.81 +/- 1.43 vs 6.56 +/- 2.36, respectively)

delayed sexual maturation
- female homozygotes display a delayed onset of puberty relative to wild-type controls

abnormal uterine cervix morphology
- only 1 of 15 female homozygotes showed cervical mucus accumulation with no other physical signs of obstruction in the uterus

thin uterus
- mutant uteri are thinner than wild-type

prolonged estrous cycle
- at 14-16 weeks of age, female homozygotes that display at least one estrous cycle show half as many cycles as wild-type females, resulting in a 2-fold increase in average cycle length

endocrine/exocrine gland phenotype

decreased corpora lutea number
- female homozygotes show an average of 1.5 +/- 2.0 corpora lutea per ovary vs 9.3 +/- 1.4 in wild-type females, even though other follicle stages are present

small ovary
- at 7 weeks of age, female homozygotes display smaller ovaries than wild-type females

decreased ovary weight
- Normal - however, mutant ovarian weight is restored to wild-type values after superovulation
- at 6-8 and 14-16 weeks of age, the average weight of mutant ovaries is reduced by 50% and 36%, respectively, relative to that of wild-type ovaries

respiratory system phenotype

decreased respiratory epithelial chloride transmembrane transport
- after treatment with a chloride-depleted solution with amiloride and forskolin, the nasal potential difference (PD) was significantly different between control mice and homozygous mice

lung inflammation
- increased inflammatory response to chronic Pseudomonas aeruginosa infection, identical to that in Cftr^tm1Unc homozygotes

growth/size/body region phenotype

postnatal growth retardation
- weighed significantly less (P 0.05) than homozygote wild-type controls at 7, 14, and 21 days of age
- at 6-8 and 14-16 weeks of age, total body weight is reduced by only 15% and 12%, respectively, thus not explaining the larger differences noted in average weight of reproductive organs (~50% and 36%, respectively)

immune system phenotype

lung inflammation
- increased inflammatory response to chronic Pseudomonas aeruginosa infection, identical to that in Cftr^tm1Unc homozygotes

increased susceptibility to bacterial infection induced morbidity/mortality
- reduced ability to respond to lung infection elicited with Pseudomonas aeruginosa- laden agarose beads

References

Zeiher BG; Eichwald E; Zabner J; Smith JJ; Puga AP; McCray PB Jr; Capecchi MR; Welsh MJ; Thomas KR. 1995. A mouse model for the delta F508 allele of cystic fibrosis. J Clin Invest 96(4):2051-64PubMed: 7560099 MGI: J:29074

Additional References

Zdebik AA; Cuffe JE; Bertog M; Korbmacher C; Jentsch TJ. 2004. Additional disruption of the ClC-2 Cl(-) channel does not exacerbate the cystic fibrosis phenotype of cystic fibrosis transmembrane conductance regulator mouse models. J Biol Chem 279(21):22276-83PubMed: 15007059 MGI: J:89831

Additional - Cftr^tm1Kth related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Cftr
- Genotyping resources and troubleshooting
Breeding Considerations

This strain is currently being maintained by mating heterozygous siblings; this is the most effective breeding strategy. Homozygous males will breed while homozygous females are very poor breeders. Expected coat color from breeding:Black
- Additional Breeding and Husbandry Support
Citation
When using the ΔF mouse strain in a publication, please cite the originating article(s) and include JAX stock #002515 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

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
> >	Heterozygous or Wild-type for Cftr<tm1Kth>

Related Products and Services

Frozen Mouse Embryo	B6.129S6-Cftr<tm1Kth>/J Frozen Embryos	$2595.00
Frozen Mouse Embryo	B6.129S6-Cftr<tm1Kth>/J Frozen Embryos	$2595.00
Frozen Mouse Embryo	B6.129S6-Cftr<tm1Kth>/J Frozen Embryos	$3373.50
Frozen Mouse Embryo	B6.129S6-Cftr<tm1Kth>/J Frozen Embryos	$3373.50

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The Jackson Laboratory's Genotype Promise

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.

Terms Of Use

General Terms and Conditions

Questions about Terms of Use

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Also Known As:ΔF

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Cftrtm1Kth

Allele Symbol: Cftrtm1Kth

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:

Genotype: Cftrtm1Kth related

Mammalian Phenotype Terms by Genotype

Genotype: Cftrtm1Kth/Cftrtm1Kthinvolves: 129S7/SvEvBrd * C57BL/6J

growth/size/body region phenotype

homeostasis/metabolism phenotype

immune system phenotype

mortality/aging

digestive/alimentary phenotype

endocrine/exocrine gland phenotype

Genotype: Cftrtm1Kth/Cftrtm1KthB6.129S7-Cftr

digestive/alimentary phenotype

mammalian phenotype

mortality/aging

reproductive system phenotype

endocrine/exocrine gland phenotype

respiratory system phenotype

growth/size/body region phenotype

immune system phenotype

References

Additional References

Additional - Cftrtm1Kth 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

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

Cftr^tm1Kth

Allele Symbol: Cftr^tm1Kth

Genotype: Cftr^tm1Kth related

Genotype: Cftr^tm1Kth/Cftr^tm1Kth
involves: 129S7/SvEvBrd * C57BL/6J

Genotype: Cftr^tm1Kth/Cftr^tm1Kth
B6.129S7-Cftr

Additional - Cftr^tm1Kth related