Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory mouse Generation N10+N3F1pN1 Generation Definitions   Donating Investigator Francesco Ramirez,   UMDNJ-Robert Wood Johnson Med Sch

Description
Both heterozygous and homozygous "mgR" mutant mice are viable with no phenotypic abnormalities at birth. The protein expressed from this mutant allele is the same size as wild-type. Skin tissues show an intermediate reduction in transcript levels compared to wild-type and the mg-delta null allele. Thus the "mgR" mutation does not completely ablate gene function (resulting in rapid death). Instead, expression is hypomorphic and conducive to studying the clinical stages precursive to animal lethality. Homozygotes develop medial calcification, the inflammatory-fibroproliferative response, and inflammation-mediated elastolysis in the natural history of dissecting aneurysm and die between 2-6 month of age with Marfan syndrome (MFS)-like manifestations.

Development
A targeting vector containing a PGKneo cassette was electroporated into (129X1/SvJ x 129S1/Sv)F1-derived R1 embryonic stem (ES) cells. An unequal crossover event inserted the PGKneo-cassette between exons 18 and 19 of the endogenous gene, resulting in no loss of endogenous sequence for this "mgR" mutant allele. Interestingly, a 67 bp long A/T-rich stretch of DNA was found to have been added at the point of transition between introns 24 and 18. Targeted ES cells were injected into C57BL/6 blastocysts and the resulting chimera's were bred to C57BL/6 mice to establish heterozygous mutants. Heterozygotes were backcrossed to C57BL/6 mice for 10 generations and then maintained by breeding heterozygotes together for many generations prior to arrival at The Jackson Laboratory.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J	(approximate)
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Fbn1

012885	B6.129-Fbn1tm1Hcd/J
000305	B6.Cg-Fbn1Tsk +/+ Bloc1s6pa/J
014632	B6.Cg-Fbn1Tsk/J

View Strains carrying other alleles of Fbn1     (3 strains)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- 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).

Marfan Syndrome; MFS

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Acromicric Dysplasia; ACMICD   (FBN1) Ectopia Lentis 1, Isolated, Autosomal Dominant; ECTOL1   (FBN1) Geleophysic Dysplasia 2; GPHYSD2   (FBN1) MASS Syndrome   (FBN1) Stiff Skin Syndrome; SSKS   (FBN1) Weill-Marchesani Syndrome 2; WMS2   (FBN1)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Fbn1^tm2Rmz/Fbn1^tm2Rmz

        involves: 129S1/Sv * 129X1/SvJ

• mortality/aging
• premature death
  • mice die at an average age of 3.8 +/- 3.4 months   (MGI Ref ID J:54081)
  • mice die within 6-9 months of life due to aortic rupture   (MGI Ref ID J:91815)
• cardiovascular system phenotype
• abnormal blood vessel morphology
  • loss of structural integrity of vessel wall   (MGI Ref ID J:54081)
  • newborns exhibit normal vasculature however with age develop late-onset vascular disease   (MGI Ref ID J:54081)
• • abnormal aorta morphology   (MGI Ref ID J:54081)
  • • abnormal aorta tunica adventitia morphology
      • 12 of 20 exhibit adventitia hyperplasia with inflammation   (MGI Ref ID J:54081)
    • abnormal aorta tunica intima morphology
      • 6 of 20 exhibit intimal hyperplasia   (MGI Ref ID J:54081)
    • abnormal aorta tunica media morphology
      • 9 of 20 exhibit medial necrosis and vasculitis   (MGI Ref ID J:54081)
      • 8 of 20 exhibit medial calcification   (MGI Ref ID J:54081)
    • • aortic elastic tissue lesions   (MGI Ref ID J:54081)
    • aortic aneurysm
      • in the most advanced aneurysms, an infiltrate of macrophages is found at the adventitial surface with extension into an obliterated tunica media   (MGI Ref ID J:54081)
  • calcified artery
    • calcification of intact elastic lamellae in the aorta is seen as early as 6 weeks of age   (MGI Ref ID J:54081)
    • calcified segments increase in frequency and coalesce over time   (MGI Ref ID J:54081)
• aortitis
  • 9 of 20 exhibit medial aorta vasculitis   (MGI Ref ID J:54081)
• hemorrhage
  • hemomediastinum   (MGI Ref ID J:54081)
• • hemopericardium   (MGI Ref ID J:54081)
  • hemothorax   (MGI Ref ID J:54081)
• respiratory system phenotype
• emphysema
  • by 6 months of age, airspace dilatation is associated with destructive changes, peribronchial inflammation, and increased expression of matrix metalloproteases, indicating emphysema   (MGI Ref ID J:91815)
• hemothorax   (MGI Ref ID J:54081)
• impaired lung alveolus development
  • impaired alveolar septation at 2 weeks of age   (MGI Ref ID J:91815)
  • immunostaining for active TGF-beta (a potential physiologic inhibitor of alveolar septation) is enhanced at 2 weeks of age   (MGI Ref ID J:91815)
• lung inflammation
  • peribronchial inflammation by 6 months of age   (MGI Ref ID J:91815)
• overexpanded pulmonary alveoli
  • significant airspace dilatation by 6 months of age   (MGI Ref ID J:91815)
• respiratory distress
  • mice with kyphosis and diaphragmatic hernia exhibit respiratory distress   (MGI Ref ID J:54081)
• skeleton phenotype
• abnormal rib morphology
  • dramatic overgrowth of the ribs   (MGI Ref ID J:54081)
• decreased bone mineral density   (MGI Ref ID J:187484)
• decreased bone trabecula number   (MGI Ref ID J:187484)
• decreased bone volume   (MGI Ref ID J:187484)
• increased length of long bones
  • long bones are at most 10% longer than in wild-type   (MGI Ref ID J:54081)
• kyphosis   (MGI Ref ID J:54081)
• growth/size phenotype
• enlarged chest
  • increase in dorsal-ventral diameter of the chest because of overgrowth of the ribs   (MGI Ref ID J:54081)
• immune system phenotype
• aortitis
  • 9 of 20 exhibit medial aorta vasculitis   (MGI Ref ID J:54081)
• lung inflammation
  • peribronchial inflammation by 6 months of age   (MGI Ref ID J:91815)
• muscle phenotype
• herniated diaphragm
  • half of mice with severe kyphosis exhibit diaphragmatic hernia with thoracic migration of abdominal contents and respiratory distress   (MGI Ref ID J:54081)
• homeostasis/metabolism phenotype
• hemopericardium   (MGI Ref ID J:54081)

View Research Applications

Research Applications

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

Cardiovascular Research
Heart Abnormalities
      aortic aneurysms

Internal/Organ Research
Heart Abnormalities
      aortic aneurysms

Research Tools
Cardiovascular Research
Internal/Organ Research

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Fbn1tm2Rmz
Allele Name		targeted mutation 2, Francesco Ramirez
Allele Type		Targeted (knock-out)
Common Name(s)		Fbn1mgR; mgR;
Mutation Made By		Francesco Ramirez,   UMDNJ-Robert Wood Johnson Med Sch
Strain of Origin		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
ES Cell Line Name		R1
ES Cell Line Strain		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
Gene Symbol and Name		Fbn1, fibrillin 1
Chromosome		2
Gene Common Name(s)		ACMICD; AI536462; ECTOL1; FBN; Fib-1; GPHYSD2; MASS; MFS1; OCTD; SGS; SSKS; Tsk; WMS; WMS2; expressed sequence AI536462; tight skin;
Molecular Note		An unequal crossover event resulted in the insertion of a neomycin selection cassette into intron 18 with no loss of coding sequences. RT-PCR analysis confirmed that correctly spliced transcripts are produced from this allele. Northern blot analysis onmRNA derived from skin samples of homozygous mice demonstrated that transcript expression was reduced approximately five-fold. Immunoprecipitation experiments on fibroblasts isolated from homozygous mice confirmed that a protein was expressed from this allele at reduced levels compared to wild-type. This is a hypomorphic allele. [MGI Ref ID J:54081]

Genotyping

Genotyping Information

Genotyping Protocols

Fbn1^tm2Rmz, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Pereira L; Lee SY; Gayraud B; Andrikopoulos K; Shapiro SD; Bunton T; Biery NJ; Dietz HC; Sakai LY; Ramirez F. 1999. Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proc Natl Acad Sci U S A 96(7):3819-23. [PubMed: 10097121]  [MGI Ref ID J:54081]

Additional References

Fbn1^tm2Rmz related

Arteaga-Solis E; Sui-Arteaga L; Kim M; Schaffler MB; Jepsen KJ; Pleshko N; Ramirez F. 2011. Material and mechanical properties of bones deficient for fibrillin-1 or fibrillin-2 microfibrils. Matrix Biol 30(3):188-94. [PubMed: 21440062]  [MGI Ref ID J:172294]

Bunton TE; Biery NJ; Myers L; Gayraud B; Ramirez F; Dietz HC. 2001. Phenotypic alteration of vascular smooth muscle cells precedes elastolysis in a mouse model of Marfan syndrome. Circ Res 88(1):37-43. [PubMed: 11139471]  [MGI Ref ID J:111116]

Carta L; Smaldone S; Zilberberg L; Loch D; Dietz HC; Rifkin DB; Ramirez F. 2009. p38 MAPK is an early determinant of promiscuous Smad2/3 signaling in the aortas of fibrillin-1 (Fbn1)-null mice. J Biol Chem 284(9):5630-6. [PubMed: 19109253]  [MGI Ref ID J:147899]

Cook JR; Smaldone S; Cozzolino C; Del Solar M; Lee-Arteaga S; Nistala H; Ramirez F. 2012. Generation of Fbn1 conditional null mice implicates the extracellular microfibrils in osteoprogenitor recruitment. Genesis 50(8):635-41. [PubMed: 22374917]  [MGI Ref ID J:187484]

Ferruzzi J; Collins MJ; Yeh AT; Humphrey JD. 2011. Mechanical assessment of elastin integrity in fibrillin-1-deficient carotid arteries: implications for Marfan syndrome. Cardiovasc Res 92(2):287-95. [PubMed: 21730037]  [MGI Ref ID J:191706]

Gayraud B; Keene DR; Sakai LY; Ramirez F. 2000. New insights into the assembly of extracellular microfibrils from the analysis of the fibrillin 1 mutation in the tight skin mouse. J Cell Biol 150(3):667-80. [PubMed: 10931876]  [MGI Ref ID J:63844]

Guo G; Munoz-Garcia B; Ott CE; Grunhagen J; Mousa SA; Pletschacher A; von Kodolitsch Y; Knaus P; Robinson PN. 2013. Antagonism of GxxPG fragments ameliorates manifestations of aortic disease in Marfan syndrome mice. Hum Mol Genet 22(3):433-43. [PubMed: 23100322]  [MGI Ref ID J:191125]

Marque V; Kieffer P; Gayraud B; Lartaud-Idjouadiene I; Ramirez F; Atkinson J. 2001. Aortic wall mechanics and composition in a transgenic mouse model of Marfan syndrome. Arterioscler Thromb Vasc Biol 21(7):1184-9. [PubMed: 11451749]  [MGI Ref ID J:128576]

Neptune ER; Frischmeyer PA; Arking DE; Myers L; Bunton TE; Gayraud B; Ramirez F; Sakai LY; Dietz HC. 2003. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet 33(3):407-11. [PubMed: 12598898]  [MGI Ref ID J:91815]

Nistala H; Lee-Arteaga S; Carta L; Cook JR; Smaldone S; Siciliano G; Rifkin AN; Dietz HC; Rifkin DB; Ramirez F. 2010. Differential effects of alendronate and losartan therapy on osteopenia and aortic aneurysm in mice with severe Marfan syndrome. Hum Mol Genet 19(24):4790-8. [PubMed: 20871099]  [MGI Ref ID J:166551]

Zacchigna L; Vecchione C; Notte A; Cordenonsi M; Dupont S; Maretto S; Cifelli G; Ferrari A; Maffei A; Fabbro C; Braghetta P; Marino G; Selvetella G; Aretini A; Colonnese C; Bettarini U; Russo G; Soligo S; Adorno M; Bonaldo P; Volpin D; Piccolo S; Lembo G; Bressan GM. 2006. Emilin1 links TGF-beta maturation to blood pressure homeostasis. Cell 124(5):929-42. [PubMed: 16530041]  [MGI Ref ID J:115889]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

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

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, heterozygous mice are bred. Homozygous mice are subfertile and die between 2-6 months of age.

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

General Supply Notes

• Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J	(approximate)
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

See Terms of Use tab for General Terms and Conditions

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.

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