Description

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. Mating System Wild-type x Heterozygote         (Female x Male)   14-OCT-11 Mating System Heterozygote x Wild-type         (Female x Male)   14-OCT-11 Species laboratory mouse Generation N10F4 (28-APR-11) Generation Definitions   Donating Investigator Harry Dietz,   Johns Hopkins Medical Institute

Description
Mice homozygous for this Fbn1 (fibrillin 1) Cys1037Gly missense mutation are small and die before two weeks of age. A similar mutation in man (Cys1039Tyr) is known to cause classic manifestations of Marfan syndrome in humans. Heterozygous mice develop proximal aortic aneurysms, mitral valve thickenings, pulmonary alveolar septation defects, mild thoracic kyphosis, and skeletal myopathy, but 90% reportedly live to one year of age.

Development
Site-directed mutagenesis was used to create a single G->T base pair alteration in the mouse gene resulting in a Cys->Gly change at amino acid 1037 (previously identified in the literature as C1039G). This corresponds with the human C1039Y mutation. The mutation was created in (129X1/SvJ x 129S1/Sv)F1- Kitl⁺-derived R1 embryonic stem (ES) cells. A loxP-flanked neomycin resistance cassette placed in intron 24 was excised through a cross with a CMV-cre mouse. This strain was backcrossed to C57BL/6 for more than nine generations by the donating laboratory.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Fbn1

005704	B6.129-Fbn1tm2Rmz/J
000305	B6.Cg-Fbn1Tsk +/+ Bloc1s6pa/J
014632	B6.Cg-Fbn1Tsk/J

View Strains carrying other alleles of Fbn1     (3 strains)

Additional Web Information

Use of MICE by companies or for-profit entities requires a license prior to shipping.

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^tm1Hcd/Fbn1⁺

        involves: 129S1/Sv * 129X1/SvJ * C57BL/6J

• cardiovascular system phenotype
• abnormal aorta wall morphology   (MGI Ref ID J:188799)
  • progressive deterioration within the medial layer, with elastic fiber fragmentation and disarray of vascular smooth muscle cells begins around 2 months of age   (MGI Ref ID J:91349)
  • however, no intimal hyperplasia, aortic inflammation, or aortic dissection are detected and life span is similar to wild-type mice   (MGI Ref ID J:91349)
• • abnormal aorta elastic fiber morphology
    • progressive fragmentation of elastic fibers within the medial wall beginning around 2 months of age   (MGI Ref ID J:91349)
    • elastic fiber calcification is occasionally seen   (MGI Ref ID J:91349)
  • increased aorta wall thickness
    • gradual thickening of the wall due to excessive deposition of amorphous matrix and increase in the number of vascular smooth muscle cells   (MGI Ref ID J:94428)
• abnormal heart left atrium morphology
  • left atrium enlargement associated with mitral valve prolapse   (MGI Ref ID J:94428)
• abnormal heart left ventricle morphology
  • left ventricle enlargement associated with mitral valve prolapse   (MGI Ref ID J:94428)
• abnormal mitral valve morphology
  • progressive increase in leaflet length and thickness during postnatal development   (MGI Ref ID J:94428)
  • leaflet length and thickness are intermediate between homozygous mutant and wild-type mice   (MGI Ref ID J:94428)
  • cells displays increased proliferation and reduced apoptosis   (MGI Ref ID J:94428)
  • in utero treatment with TGFB neutralizing antibodies at E14.5 and E17.5 rescues mitral valve morphology   (MGI Ref ID J:94428)
• • mitral valve prolapse
    • mitral valve prolapse and regurgitation at 9 months of age   (MGI Ref ID J:94428)
• respiratory system phenotype
• overexpanded pulmonary alveoli
  • distal airspace widening without inflammation or tissue damage   (MGI Ref ID J:91349)
• skeleton phenotype
• abnormal skeleton morphology
  • gradual postnatal development of skeletal abnormalities similar to those in other hypomorphic mouse models of Marfan Syndrome   (MGI Ref ID J:91349)
• • abnormal rib morphology
    • postnatal overgrowth   (MGI Ref ID J:91349)
  • kyphosis
    • gradual postnatal development   (MGI Ref ID J:91349)

Fbn1^tm1Hcd/Fbn1^tm1Hcd

        involves: 129S1/Sv * 129X1/SvJ * C57BL/6J

• mortality/aging
• complete postnatal lethality   (MGI Ref ID J:91349)
  • die at P7 - P10 from aortic dissection   (MGI Ref ID J:94428)
• cardiovascular system phenotype
• abnormal blood vessel morphology
  • die from vascular catastrophe indistinguishable from mice homozygous for severe hypomorphic alleles   (MGI Ref ID J:91349)
• • aortic dissection   (MGI Ref ID J:94428)
• abnormal mitral valve morphology
  • progressive increase in leaflet length and thickness during postnatal development first becoming significantly different from wild-type at P6.5 and P4.5, respectively   (MGI Ref ID J:94428)
  • the leaflet tips fold back and fuse to more proximal segments   (MGI Ref ID J:94428)
  • cells displays increased proliferation and reduced apoptosis   (MGI Ref ID J:94428)
  • in utero treatment with TGFB neutralizing antibodies at E14.5 and E17.5 reduces mitral valve overgrowth   (MGI Ref ID J:94428)

View Research Applications

Research Applications

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

Cardiovascular Research
Heart Abnormalities
      aortic aneurysms

Developmental Biology Research
Internal/Organ Defects
      lung
Skeletal Defects

Internal/Organ Research
Lung Defects

Mouse/Human Gene Homologs
Marfan syndrome

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Fbn1tm1Hcd
Allele Name		targeted mutation 1, Harry C Dietz
Allele Type		Targeted (knock-in)
Common Name(s)		Fbn1C1037G; Fbn1C1039G;
Mutation Made By		Harry Dietz,   Johns Hopkins Medical Institute
Strain of Origin		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
Promoter		Fbn1, fibrillin 1, mouse, laboratory
Molecular Note		Site-directed mutagenesis was used to create a single G->T base pair alteration in the mouse gene resulting in a Cys->Gly change at amino acid 1037 (previously identified in the literature as C1039G). This corresponds with the human C1039Y mutation. The floxed neo selection cassette was removed by crossing to a ubiquitously expressing Cre mouse line. [MGI Ref ID J:91349]

Genotyping

Genotyping Information

Genotyping Protocols

Fbn1^tm1Hcd, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Judge DP; Biery NJ; Keene DR; Geubtner J; Myers L; Huso DL; Sakai LY; Dietz HC. 2004. Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J Clin Invest 114(2):172-81. [PubMed: 15254584]  [MGI Ref ID J:91349]

Additional References

Fbn1^tm1Hcd related

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]

Chung AW; Au Yeung K; Cortes SF; Sandor GG; Judge DP; Dietz HC; van Breemen C. 2007. Endothelial dysfunction and compromised eNOS/Akt signaling in the thoracic aorta during the progression of Marfan syndrome. Br J Pharmacol 150(8):1075-83. [PubMed: 17339838]  [MGI Ref ID J:148671]

Chung AW; Au Yeung K; Sandor GG; Judge DP; Dietz HC; van Breemen C. 2007. Loss of elastic fiber integrity and reduction of vascular smooth muscle contraction resulting from the upregulated activities of matrix metalloproteinase-2 and -9 in the thoracic aortic aneurysm in Marfan syndrome. Circ Res 101(5):512-22. [PubMed: 17641224]  [MGI Ref ID J:140291]

Cohn RD; van Erp C; Habashi JP; Soleimani AA; Klein EC; Lisi MT; Gamradt M; Ap Rhys CM; Holm TM; Loeys BL; Ramirez F; Judge DP; Ward CW; Dietz HC. 2007. Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states. Nat Med 13(2):204-210. [PubMed: 17237794]  [MGI Ref ID J:117885]

Habashi JP; Doyle JJ; Holm TM; Aziz H; Schoenhoff F; Bedja D; Chen Y; Modiri AN; Judge DP; Dietz HC. 2011. Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism. Science 332(6027):361-5. [PubMed: 21493863]  [MGI Ref ID J:171337]

Habashi JP; Judge DP; Holm TM; Cohn RD; Loeys BL; Cooper TK; Myers L; Klein EC; Liu G; Calvi C; Podowski M; Neptune ER; Halushka MK; Bedja D; Gabrielson K; Rifkin DB; Carta L; Ramirez F; Huso DL; Dietz HC. 2006. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312(5770):117-21. [PubMed: 16601194]  [MGI Ref ID J:107296]

Holm TM; Habashi JP; Doyle JJ; Bedja D; Chen Y; van Erp C; Lindsay ME; Kim D; Schoenhoff F; Cohn RD; Loeys BL; Thomas CJ; Patnaik S; Marugan JJ; Judge DP; Dietz HC. 2011. Noncanonical TGFbeta signaling contributes to aortic aneurysm progression in Marfan syndrome mice. Science 332(6027):358-61. [PubMed: 21493862]  [MGI Ref ID J:171338]

Lindsay ME; Schepers D; Bolar NA; Doyle JJ; Gallo E; Fert-Bober J; Kempers MJ; Fishman EK; Chen Y; Myers L; Bjeda D; Oswald G; Elias AF; Levy HP; Anderlid BM; Yang MH; Bongers EM; Timmermans J; Braverman AC; Canham N; Mortier GR; Brunner HG; Byers PH; Van Eyk J; Van Laer L; Dietz HC; Loeys BL. 2012. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet 44(8):922-7. [PubMed: 22772368]  [MGI Ref ID J:188799]

Matt P; Schoenhoff F; Habashi J; Holm T; Van Erp C; Loch D; Carlson OD; Griswold BF; Fu Q; De Backer J; Loeys B; Huso DL; McDonnell NB; Van Eyk JE; Dietz HC. 2009. Circulating transforming growth factor-beta in Marfan syndrome. Circulation 120(6):526-32. [PubMed: 19635970]  [MGI Ref ID J:172339]

Merk DR; Chin JT; Dake BA; Maegdefessel L; Miller MO; Kimura N; Tsao PS; Iosef C; Berry GJ; Mohr FW; Spin JM; Alvira CM; Robbins RC; Fischbein MP. 2012. miR-29b participates in early aneurysm development in Marfan syndrome. Circ Res 110(2):312-24. [PubMed: 22116819]  [MGI Ref ID J:192708]

Ng CM; Cheng A; Myers LA; Martinez-Murillo F; Jie C; Bedja D; Gabrielson KL; Hausladen JM; Mecham RP; Judge DP; Dietz HC. 2004. TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. J Clin Invest 114(11):1586-92. [PubMed: 15546004]  [MGI Ref ID J:94428]

Pearson GD; Devereux R; Loeys B; Maslen C; Milewicz D; Pyeritz R; Ramirez F; Rifkin D; Sakai L; Svensson L; Wessels A; Van Eyk J; Dietz HC. 2008. Report of the National Heart, Lung, and Blood Institute and National Marfan Foundation Working Group on research in Marfan syndrome and related disorders. Circulation 118(7):785-91. [PubMed: 18695204]  [MGI Ref ID J:158045]

Van Herck JL; De Meyer GR; Martinet W; Van Hove CE; Foubert K; Theunis MH; Apers S; Bult H; Vrints CJ; Herman AG. 2009. Impaired fibrillin-1 function promotes features of plaque instability in apolipoprotein E-deficient mice. Circulation 120(24):2478-87. [PubMed: 19948973]  [MGI Ref ID J:168127]

Xu H; Krolikowski JG; Jones DW; Ge ZD; Pagel PS; Pritchard KA Jr; Weihrauch D. 2012. 4F decreases IRF5 expression and activation in hearts of tight skin mice. PLoS One 7(12):e52046. [PubMed: 23251680]  [MGI Ref ID J:195662]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	When maintained as a live colony, heterozygotes may be bred. Homozygotes die before two weeks of age.
Mating System	Wild-type x Heterozygote         (Female x Male)   14-OCT-11
	Heterozygote x Wild-type         (Female x Male)   14-OCT-11

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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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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