FcRn-deficient hFcRn(Tg99) BXSB.Yaa mice (BXSB.FcRn-/- hFcRn(Tg99) or BXSB.Yaa FcRn-/- hFcRn(Tg99)) are a BXSB-congenic strain with endogenous mouse FcRn expression knocked out and replaced with expression of the human FcRn α-chain transgene under the control of its natural human promoter. These mice may be useful in evaluating thepharmacokinetics/pharmacodynamics of human immunoglobulin G and/or human therapeutic antibodies in an autoimmune disease setting.
Dr. Derry Roopenian, The Jackson Laboratory
Genetic Background | Generation |
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|
Allele Type | Gene Symbol | Gene Name |
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Spontaneous | Yaa | accelerated autoimmunity and lymphoproliferation transposition |
Allele Type | Gene Symbol | Gene Name |
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Targeted (Null/Knockout) | Fcgrt | Fc receptor, IgG, alpha chain transporter |
Allele Type |
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Transgenic (Inserted expressed sequence, Humanized sequence) |
BXSB/MpJ inbred males (Stock No. 000740) develop a spontaneous lupus-like autoimmune syndrome: mortality starts at ~13 weeks of age with 50% lethality by ~30 weeks and 76% lethality by ~40 weeks. BXSB/MpJ inbred females develop a greatly attenuated form of autoimmune disease because they lack Yaa.
BXSB.FcRn-/- mice are described and available as Stock No. 021455. Mice homozygous for the FcRn knockout allele (FcRn-/-) lack the Fc receptor (FcRn), which normally functions to enhance the presentation of immune-complexed antigens by MHC class II molecules and is critical for maintaining normal concentrations of immunoglobulin G (IgG) antibodies and serum albumin. BXSB.FcRn-/- mice are viable and fertile, with ~50% reduction in IgG. Both homozygous and heterozygous mice develop spontaneous lupus-like autoimmune syndrome similarly to BXSB/MpJ inbred mice.
Stock No. 025099: FcRn-deficient hFcRn(Tg99) BXSB.Yaa mice (BXSB.FcRn-/- hFcRn(Tg99) or BXSB.Yaa FcRn-/- hFcRn(Tg99)) are a BXSB-congenic strain with endogenous mouse FcRn expression knocked out and replaced with expression of the human FcRn α-chain transgene under the control of its natural human promoter. Mice homozygous for the FcRn null allele and hemizygous for the hFcRn(Tg99) transgene (FcRn-/- hFcRn(Tg99)) are viable and fertile. The donating investigator reports that FcRn-/- hFcRn(Tg99) animals develop spontaneous lupus-like autoimmune syndrome similarly to that of BXSB.FcRn-/- mice and BXSB/MpJ inbred mice. While the phenotype of FcRn-/- hFcRn(Tg99) mice is not fully characterized to date (June 2014), they may be expected to have reduced IgG levels. Because human FcRn protects human IgG and does not protect mouse IgG, these FcRn-/- hFcRn(Tg99) mice are ideal for evaluating the pharmacokinetics/pharmacodynamics of human therapeutic antibodies in an autoimmune disease setting.
Of note, C57BL/6J-congenic mice harboring the FcRn null allele and the same transgene with different insertion site [hFcRn(Tg32)] are described and available from The Jackson Laboratory Repository as Stock No. 014565.
BXSB.FcRn-/- hFcRn(Tg99) mice are a BXSB-congenic "humanized" FcRn strain; carrying the FcRn null allele and a transgene expressing human FcRn. The knockout mutation and human transgene are described below.
The FcRn knockout allele (FcRn-; Fcgrttm1Dcr) was designed by Dr. Derry C. Roopenian (The Jackson Laboratory) to replace 1588 nucleotides (encoding promoter sequence 5' of the transcriptional start site, exon1, intron 2, and most of exon2) of the Fcgrt gene (Fc receptor, IgG, alpha chain transporter) on chromosome 7 with a PGK-Neor cassette. The vector was electroporated into 129X1/SvJ-derived ESV/J-1182 (RW4) embryonic stem cells. FcRn- mice backcrossed for at least 12 generations onto the BXSB/MpJ genetic background (BXSB.FcRn-) are described and available as Stock No. 021455. BXSB.FcRn- mice were used for breeding as below.
The hFcRn transgenic line 99 [hFcRn(Tg99)] mice were created by Dr. Roopenian. It has the same transgene construct as hFcRn transgenic line 32 (Stock No. 014565). The transgene genomic insertion sites of line 99 and line 32 are not characterized to date. The hFcRn transgene is an ~34 kbp cosmid clone with the complete ~11 kbp human FCGRT gene (as well as ~10 kbp of 5' and 3' flanking sequences). This construct was microinjected into fertilized BXSB/MpJ mouse eggs. Founder animal Tg#99 was bred to BXSB/MpJ. The resulting transgenic colony was maintained on the BXSB/MpJ genetic background by breeding transgenic mice together for several generations. These BXSB.hFcRn(Tg99) mice were used for breeding as below.
To generate the BXSB.FcRn- hFcRn(Tg99) animals (Stock No. 025099), The Jackson Laboratory Repository Autoimmune Resource bred BXSB.FcRn- and BXSB.hFcRn(Tg99) together. Male mice have the BXSB/MpJ-derived Y chromosome that contains the Y-linked autoimmune accelerator locus (Yaa).
Expressed Gene | FCGRT, Fc fragment of IgG receptor and transporter, human |
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Site of Expression |
Depending upon the experiment, the following may be appropriate control strain(s):
BXSB.FcRn-/-, non-carrier Tg(FCGRT)mice
BXSB/MpJ inbred mice (Stock No. 000740).
Allele Name | accelerated autoimmunity and lymphoproliferation |
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Allele Type | Spontaneous |
Allele Synonym(s) | Is(XOfd1-Mid1;Y)1Mp; Tp(X;Y)1Ekw |
Gene Symbol and Name | Yaa, accelerated autoimmunity and lymphoproliferation transposition |
Gene Synonym(s) | |
Strain of Origin | SB/Le |
Chromosome | Y |
Molecular Note | An approximately 4 MB region of the X chromosome that includes at least 13 known genes (spanning from Ofd1 to Mid1) was translocated to the Y chromosome adjacent to the pseudoautosomal region. Increased RNA expression of Msl3, Tlr7, Tmsb4x and Rab9 was detected in follicular B cells. |
Allele Name | targeted mutation 1, Derry C Roopenian |
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Allele Type | Targeted (Null/Knockout) |
Allele Synonym(s) | FcRn- |
Gene Symbol and Name | Fcgrt, Fc receptor, IgG, alpha chain transporter |
Gene Synonym(s) | |
Strain of Origin | 129X1/SvJ |
Chromosome | 7 |
Molecular Note | Sequence from exon 1 and part of exon2 was replaced with a PGK-neo cassette. Quantitative PCR of liver cDNA indicated the absence of mRNA. Western blot analysis of neonatal intestinal extracts failed to reveal protein product. |
Allele Name | transgene insertion 99, Derry C Roopenian |
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Allele Type | Transgenic (Inserted expressed sequence, Humanized sequence) |
Allele Synonym(s) | hFcRn(Tg99) |
Gene Symbol and Name | Tg(FCGRT)99Dcr, transgene insertion 99, Derry C Roopenian |
Gene Synonym(s) | |
Promoter | FCGRT, Fc fragment of IgG receptor and transporter, human |
Expressed Gene | FCGRT, Fc fragment of IgG receptor and transporter, human |
Strain of Origin | BXSB/MpJ |
Chromosome | UN |
Molecular Note | A 34Kb fragment of a BAC containing the entire human FCGRT , Fc fragment of IgG, receptor, transporter, alpha, gene (approximately 11kb) and approximately 10kb of flanking sequence was sublconed into a SuperCos vector. Founder line 99 was established. |
To maintain the live colony, mice homozygous for the FcRn null allele and hemizygous for the hFcRn(Tg99) transgene (FcRn-/- hFcRn(Tg99)) may be bred to mice homozygous for the FcRn null allele and wildtype (noncarrier) for the hFcRn(Tg99) transgene. Both FcRn-/- hFcRn(Tg99) and FcRn+/- hFcRn(Tg99) mice develop spontaneous lupus-like autoimmune syndrome similarly to BXSB/MpJ inbred mice (Stock No. 000740): mortality in males starts at ~13 weeks of age with 50% lethality by ~30 weeks and 76% lethality by ~40 weeks. Females develop a greatly attenuated form of autoimmune disease because they lack Yaa. The expected coat color is white-bellied agouti.
When using the BXSB.Cg-Fcgrttm1Dcr Tg(FCGRT)99Dcr/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #025099 in your Materials and Methods section.
Facility Barrier Level Descriptions
Service/Product | Description | Price |
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Heterozygous for Fcgrt<tm1Dcr>, Hemizygous or non carrier for Tg(FCGRT)99Dcr |
Frozen Mouse Embryo | BXSB.Cg-Fcgrt<tm1Dcr> Tg(FCGRT)99Dcr/J | $2595.00 |
Frozen Mouse Embryo | BXSB.Cg-Fcgrt<tm1Dcr> Tg(FCGRT)99Dcr/J | $2595.00 |
Frozen Mouse Embryo | BXSB.Cg-Fcgrt<tm1Dcr> Tg(FCGRT)99Dcr/J | $3373.50 |
Frozen Mouse Embryo | BXSB.Cg-Fcgrt<tm1Dcr> Tg(FCGRT)99Dcr/J | $3373.50 |
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