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 Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse   Donating Investigator Ashok B Kulkarni,   NIDCR NIH

Description
This knockout is a model for Fabry disease, an X-linked inherited metabolic disorder that is caused by a deficiency of alpha-galactosidase A. In Fabry disease, deposition of glycosphingolipids with alpha-galactosyl terminal moieties causes renal failure, myocardial infarctions, and strokes.

Development
The targeting vector was constructed using the genomic clones of the mouse alpha galactosidase A gene isolated from the 129/SvJ mouse genomic library. The vector carries a 1 kb deletion spanning part of exon III and intron III. At the site of the deletion, the neomycin resistance gene was inserted as a positive selection marker.

Control Information

	Control
	101045 B6129SF2/J
Considerations for Choosing Controls

Related Strains

Strains carrying   Gla^tm1Kul allele

012625

B6;129-Glatm1Kul wblo/GrsrJ

View Strains carrying   Gla^tm1Kul     (1 strain)

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).

Fabry Disease

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Gla^tm1Kul/Y

        involves: 129S4/SvJae * C57BL/6

• renal/urinary system phenotype
• abnormal kidney morphology
  • electron microscopy reveales concentric lamellar incusions within lysosomes of renal tubular cells   (MGI Ref ID J:39394)
  • marked accumulation of ceramidetrihexoside in the liver and kidneys   (MGI Ref ID J:39394)
  • mice otherwise appear healthy up to 10-14 weeks of age   (MGI Ref ID J:39394)
• liver/biliary system phenotype
• abnormal liver morphology
  • marked accumulation of ceramidetrihexoside in the liver and kidneys   (MGI Ref ID J:39394)
• cellular phenotype
• abnormal cell morphology
  • accumulation of material containing terminal alpha-galactosyl residues in cultured embryonic fibroblasts   (MGI Ref ID J:39394)
• cardiovascular system phenotype
• abnormal cardiovascular system physiology
  • mutant males exhibit mild diastolic left ventricular dysfunction as indicated by a decrease in the maximal diastolic velocity of the mitral annulus, without change in the isovolumic relaxation time   (MGI Ref ID J:187258)
  • however, global left ventricular systolic function is similar to wild-type mice   (MGI Ref ID J:187258)
  • treatment with a single dose of agalsidase-beta, a type of enzyme replacement therapy, does not affect the left ventricular hypertrophy, function or heart rate, but improves the mRNA signals of early cardiac remodeling   (MGI Ref ID J:187258)
• • cardiomyopathy
    • mild hypertrophic cardiomyopathy   (MGI Ref ID J:187258)
  • decreased heart rate
    • heart rate is slower in 4 month old males   (MGI Ref ID J:187258)
  • decreased systemic arterial systolic blood pressure
    • lower systolic blood pressure in males than in wild-type males   (MGI Ref ID J:187258)
  • irregular heartbeat
    • premature atrial contractions are more frequently observed in mutant males than in wild-type males   (MGI Ref ID J:187258)
  • prolonged RR interval
    • males exhibit prolonged RR intervals   (MGI Ref ID J:187258)
    • however, no differences in PQ, QRS, or corrected QT intervals   (MGI Ref ID J:187258)
• aorta dilation
  • increase in the aortic diameter during diastole indicating ascending aortic dilation, however it is not associated with aortic valvular regurgitation   (MGI Ref ID J:187258)
• heart left ventricle hypertrophy
  • increase in left ventricular mass at 4 months of age when normalized to body weight   (MGI Ref ID J:187258)
• increased heart weight
  • heart weight is increased, when normalized to body weight or tibial weight   (MGI Ref ID J:187258)
• muscle phenotype
• cardiomyopathy
  • mild hypertrophic cardiomyopathy   (MGI Ref ID J:187258)

View Research Applications

Research Applications

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

Gla^tm1Kul related

Metabolism Research

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Glatm1Kul
Allele Name		targeted mutation 1, Ashok B Kulkarni
Allele Type		Targeted (knock-out)
Common Name(s)		Gla-; alpha-Gal A -/0; alpha-galA-;
Mutation Made By		Ashok Kulkarni,   NIDCR NIH
Strain of Origin		129S4/SvJae
ES Cell Line Name		J1
ES Cell Line Strain		129S4/SvJae
Gene Symbol and Name		Gla, galactosidase, alpha
Chromosome		X
Gene Common Name(s)		Ags; GALA; alpha-galactosidase;
Molecular Note		A 1kb genomic fragment containing part of exon 3 and intron 3 was replaced by a neomycin resistance cassette. [MGI Ref ID J:39394]

Genotyping

Genotyping Information

Genotyping Protocols

Gla^tm1Kul, Melt Curve Analysis
Gla^tm1Kul, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Ohshima T; Murray GJ; Swaim WD; Longenecker G; Quirk JM; Cardarelli CO; Sugimoto Y; Pastan I; Gottesman MM; Brady RO; Kulkarni AB. 1997. alpha-Galactosidase A deficient mice: a model of Fabry disease. Proc Natl Acad Sci U S A 94(6):2540-4. [PubMed: 9122231]  [MGI Ref ID J:39394]

Additional References

Gla^tm1Kul related

Abe A; Gregory S; Lee L; Killen PD; Brady RO; Kulkarni A; Shayman JA. 2000. Reduction of globotriaosylceramide in fabry disease mice by substrate deprivation J Clin Invest 105(11):1563-71. [PubMed: 10841515]  [MGI Ref ID J:62764]

Aerts JM; Groener JE; Kuiper S; Donker-Koopman WE; Strijland A; Ottenhoff R; van Roomen C; Mirzaian M; Wijburg FA; Linthorst GE; Vedder AC; Rombach SM; Cox-Brinkman J; Somerharju P; Boot RG; Hollak CE; Brady RO; Poorthuis BJ. 2008. Elevated globotriaosylsphingosine is a hallmark of Fabry disease. Proc Natl Acad Sci U S A 105(8):2812-7. [PubMed: 18287059]  [MGI Ref ID J:132814]

Balreira A; Macedo MF; Girao C; Rodrigues LG; Oliveira JP; Sa Miranda MC; Arosa FA. 2008. Anomalies in conventional T and invariant natural killer T-cell populations in Fabry mice but not in Fabry patients. Br J Haematol 143(4):601-4. [PubMed: 18986392]  [MGI Ref ID J:145615]

Bodary PF; Shen Y; Vargas FB; Bi X; Ostenso KA; Gu S; Shayman JA; Eitzman DT. 2005. Alpha-galactosidase A deficiency accelerates atherosclerosis in mice with apolipoprotein E deficiency Circulation 111(5):629-32. [PubMed: 15668341]  [MGI Ref ID J:108541]

Boskey AL; Goldberg M; Kulkarni A; Gomez S. 2006. Infrared imaging microscopy of bone: illustrations from a mouse model of Fabry disease. Biochim Biophys Acta 1758(7):942-7. [PubMed: 16697974]  [MGI Ref ID J:115866]

Cilmi SA; Karalius BJ; Choy W; Smith RN; Butterton JR. 2006. Fabry disease in mice protects against lethal disease caused by Shiga toxin-expressing enterohemorrhagic Escherichia coli. J Infect Dis 194(8):1135-40. [PubMed: 16991089]  [MGI Ref ID J:147262]

Darmoise A; Teneberg S; Bouzonville L; Brady RO; Beck M; Kaufmann SH; Winau F. 2010. Lysosomal alpha-galactosidase controls the generation of self lipid antigens for natural killer T cells. Immunity 33(2):216-28. [PubMed: 20727792]  [MGI Ref ID J:163911]

Durant B; Forni S; Sweetman L; Brignol N; Meng XL; Benjamin ER; Schiffmann R; Shen JS. 2011. Sex differences of urinary and kidney globotriaosylceramide and lyso-globotriaosylceramide in Fabry mice. J Lipid Res 52(9):1742-6. [PubMed: 21747096]  [MGI Ref ID J:175547]

Eitzman DT; Bodary PF; Shen Y; Khairallah CG; Wild SR; Abe A; Shaffer-Hartman J; Shayman JA. 2003. Fabry disease in mice is associated with age-dependent susceptibility to vascular thrombosis. J Am Soc Nephrol 14(2):298-302. [PubMed: 12538729]  [MGI Ref ID J:103145]

Gadola SD; Silk JD; Jeans A; Illarionov PA; Salio M; Besra GS; Dwek R; Butters TD; Platt FM; Cerundolo V. 2006. Impaired selection of invariant natural killer T cells in diverse mouse models of glycosphingolipid lysosomal storage diseases. J Exp Med 203(10):2293-303. [PubMed: 16982810]  [MGI Ref ID J:124639]

Ishii S; Yoshioka H; Mannen K; Kulkarni AB; Fan JQ. 2004. Transgenic mouse expressing human mutant alpha-galactosidase A in an endogenous enzyme deficient background: a biochemical animal model for studying active-site specific chaperone therapy for Fabry disease. Biochim Biophys Acta 1690(3):250-7. [PubMed: 15511632]  [MGI Ref ID J:115497]

Itoh Y; Esaki T; Cook M; Qasba P; Shimoji K; Alroy J; Brady RO; Sokoloff L; Moore DF. 2001. Local and global cerebral blood flow and glucose utilization in the alpha-galactosidase A knockout mouse model of Fabry disease. J Neurochem 79(6):1217-24. [PubMed: 11752062]  [MGI Ref ID J:73481]

Karst SY; Ward-Bailey PF; Berstrom DE; Donahue LR; Davisson-Fahey MT. 2010. Wobbly locomotion; a new neurological mutation causing an abnormal gait MGI Direct Data Submission :.  [MGI Ref ID J:159015]

Macedo MF; Quinta R; Pereira CS; Sa Miranda MC. 2012. Enzyme replacement therapy partially prevents invariant Natural Killer T cell deficiency in the Fabry disease mouse model. Mol Genet Metab 106(1):83-91. [PubMed: 22425450]  [MGI Ref ID J:183390]

Marshall J; Ashe KM; Bangari D; McEachern K; Chuang WL; Pacheco J; Copeland DP; Desnick RJ; Shayman JA; Scheule RK; Cheng SH. 2010. Substrate reduction augments the efficacy of enzyme therapy in a mouse model of Fabry disease. PLoS One 5(11):e15033. [PubMed: 21124789]  [MGI Ref ID J:167321]

Meng XL; Shen JS; Kawagoe S; Ohashi T; Brady RO; Eto Y. 2010. Induced pluripotent stem cells derived from mouse models of lysosomal storage disorders. Proc Natl Acad Sci U S A 107(17):7886-91. [PubMed: 20385825]  [MGI Ref ID J:159373]

Moore DF; Gelderman MP; Ferreira PA; Fuhrmann SR; Yi H; Elkahloun A; Lix LM; Brady RO; Schiffmann R; Goldin E. 2007. Genomic abnormalities of the murine model of Fabry disease after disease-related perturbation, a systems biology approach. Proc Natl Acad Sci U S A 104(19):8065-70. [PubMed: 17470787]  [MGI Ref ID J:121587]

Nguyen Dinh Cat A; Escoubet B; Agrapart V; Griol-Charhbili V; Schoeb T; Feng W; Jaimes E; Warnock DG; Jaisser F. 2012. Cardiomyopathy and response to enzyme replacement therapy in a male mouse model for Fabry disease. PLoS One 7(5):e33743. [PubMed: 22574107]  [MGI Ref ID J:187258]

Noben-Trauth K; Neely H; Brady RO. 2007. Normal hearing in alpha-galactosidase A-deficient mice, the mouse model for Fabry disease. Hear Res 234(1-2):10-4. [PubMed: 17933476]  [MGI Ref ID J:127432]

Ohashi T; Iizuka S; Ida H; Eto Y. 2008. Reduced alpha-Gal A enzyme activity in Fabry fibroblast cells and Fabry mice tissues induced by serum from antibody positive patients with Fabry disease. Mol Genet Metab 94(3):313-8. [PubMed: 18456533]  [MGI Ref ID J:137548]

Ohshima T; Schiffmann R; Murray GJ; Kopp J; Quirk JM; Stahl S; Chan CC; Zerfas P; Tao-Cheng JH; Ward JM; Brady RO; Kulkarni AB. 1999. Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice. Proc Natl Acad Sci U S A 96(11):6423-7. [PubMed: 10339603]  [MGI Ref ID J:110917]

Park JL; Shu L; Shayman JA. 2009. Differential involvement of COX1 and COX2 in the vasculopathy associated with the alpha-galactosidase A-knockout mouse. Am J Physiol Heart Circ Physiol 296(4):H1133-40. [PubMed: 19202000]  [MGI Ref ID J:150899]

Park S; Kim JA; Joo KY; Choi S; Choi EN; Shin JA; Han KH; Jung SC; Suh SH. 2011. Globotriaosylceramide leads to K(Ca)3.1 channel dysfunction: a new insight into endothelial dysfunction in Fabry disease. Cardiovasc Res 89(2):290-9. [PubMed: 20971723]  [MGI Ref ID J:186885]

Porubsky S; Speak AO; Salio M; Jennemann R; Bonrouhi M; Zafarulla R; Singh Y; Dyson J; Luckow B; Lehuen A; Malle E; Muthing J; Platt FM; Cerundolo V; Grone HJ. 2012. Globosides but not isoglobosides can impact the development of invariant NKT cells and their interaction with dendritic cells. J Immunol 189(6):3007-17. [PubMed: 22875802]  [MGI Ref ID J:189359]

Rodrigues LG; Ferraz MJ; Rodrigues D; Pais-Vieira M; Lima D; Brady RO; Sousa MM; Sa-Miranda MC. 2009. Neurophysiological, behavioral and morphological abnormalities in the Fabry knockout mice. Neurobiol Dis 33(1):48-56. [PubMed: 18848893]  [MGI Ref ID J:144595]

Shen Y; Bodary PF; Vargas FB; Homeister JW; Gordon D; Ostenso KA; Shayman JA; Eitzman DT. 2006. Alpha-galactosidase A deficiency leads to increased tissue fibrin deposition and thrombosis in mice homozygous for the factor V Leiden mutation. Stroke 37(4):1106-8. [PubMed: 16514103]  [MGI Ref ID J:135765]

Shu L; Park JL; Byun J; Pennathur S; Kollmeyer J; Shayman JA. 2009. Decreased nitric oxide bioavailability in a mouse model of Fabry disease. J Am Soc Nephrol 20(9):1975-85. [PubMed: 19628671]  [MGI Ref ID J:166329]

Shu L; Shayman JA. 2007. Caveolin-associated accumulation of globotriaosylceramide in the vascular endothelium of alpha-galactosidase A null mice. J Biol Chem 282(29):20960-7. [PubMed: 17535804]  [MGI Ref ID J:124604]

Tajima Y; Kawashima I; Tsukimura T; Sugawara K; Kuroda M; Suzuki T; Togawa T; Chiba Y; Jigami Y; Ohno K; Fukushige T; Kanekura T; Itoh K; Ohashi T; Sakuraba H. 2009. Use of a modified alpha-N-acetylgalactosaminidase in the development of enzyme replacement therapy for Fabry disease. Am J Hum Genet 85(5):569-80. [PubMed: 19853240]  [MGI Ref ID J:158195]

Takenaka T; Murray GJ; Qin G; Quirk JM; Ohshima T; Qasba P; Clark K; Kulkarni AB; Brady RO; Medin JA. 2000. Long-term enzyme correction and lipid reduction in multiple organs of primary and secondary transplanted Fabry mice receiving transduced bone marrow cells. Proc Natl Acad Sci U S A 97(13):7515-20. [PubMed: 10840053]  [MGI Ref ID J:62906]

Togawa T; Kawashima I; Kodama T; Tsukimura T; Suzuki T; Fukushige T; Kanekura T; Sakuraba H. 2010. Tissue and plasma globotriaosylsphingosine could be a biomarker for assessing enzyme replacement therapy for Fabry disease. Biochem Biophys Res Commun 399(4):716-20. [PubMed: 20692233]  [MGI Ref ID J:164895]

Zhou D; Cantu C rd; Sagiv Y; Schrantz N; Kulkarni AB; Qi X; Mahuran DJ; Morales CR; Grabowski GA; Benlagha K; Savage P; Bendelac A; Teyton L. 2004. Editing of CD1d-bound lipid antigens by endosomal lipid transfer proteins. Science 303(5657):523-7. [PubMed: 14684827]  [MGI Ref ID J:90443]

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	The submitter maintains the strain on a mixed background (B6,129) as homozygotes (brother x sister matings).

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
	101045 B6129SF2/J
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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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.

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