These TIN2DC-cond mice contain a mutation in the Tinf2 gene, similar to that found in humans with the bone marrow failure syndrome dyskeratosis congenital (DC).
Titia de Lange, The Rockefeller University
Genetic Background | Generation |
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|
Allele Type | Gene Symbol | Gene Name |
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Targeted (Conditional ready (e.g. floxed), Humanized sequence, No functional change) | Tinf2 | Terf1 (TRF1)-interacting nuclear factor 2 |
TIN2DC-cond mice contain the amino acid mutation K267E in exon 6 of the Terf1 (TRF1)-interacting nuclear factor 2 (Tinf2) gene. This mutation introduces a lysine-to-glutamate mutation, analogous to mutations found in patients with dyskeratosis congenital (DC). These mice also contain a loxP-flanked Puro-4x polyA STOP cassette between exons 2 and 3. In the absence of Cre in TIN2+/DC-cond floxed mice, Tinf2 expression is prevented by the STOP sequence. After cre-mediated removal of the loxP-flanked STOP cassette, TIN2+/DC mice express TIN2 K267E DC in all cells where Cre recombinase is expressed. Hemizygous mice are viable and fertile. DC is a progressive bone marrow failure syndrome characterized by a mucocutaneous triad of oral leukoplakia, nail dystrophy, abnormal skin pigmentation, and a predisposition to cancer. TINF2 is a component of the shelterin protein complex which is required for the maintenance and protection of telomeres. In DC, mutations in shelterin complexes lead to impaired maintenance of telomeres and reduced telomere length. Rapidly dividing cells, such as cells of the nail beds, hair follicles, skin, lining of the mouth (oral mucosa), and bone marrow, are affected by shortened telomeres.
When bred to mice with widespread Cre-recombinase expression (for example, Tg(CMV-cre)1Cgn - Stock No. 006054) , TIN2+/DC mice exhibit gradual telomere shortening. After several generations, this telomere shortening results in diminished fecundity due to testicular and seminiferous tubule atrophy. These mice also showed indices of pancytopenia that resembled a mild form of the hematological defects in DC patients, including a decrease in the numbers of reticulocytes, total lymphocytes, neutrophils and platelets.
A targeting construct was designed to insert a loxP-flanked transcriptional STOP cassette (Puro-4x polyA) between exons 2 and 3, and a frt-flanked neomycin (neo) resistance cassette downstream of exon 7 of the Terf1 (TRF1)-interacting nuclear factor 2 (Tinf2) gene. A point mutation was introduced in amino acid 267 in exon 6, corresponding to human amino acid 280, resulting in a lysine-to-glutamate mutation, (K267E) commonly found in patients with dyskeratosis congenital (DC). This targeting construct was electroporated into B6(Cg)-Tyrc-2J/J-derived embryonic stem (ES) cells and correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric mice were bred to FLPe deleter mice on a C57BL/6J background to remove the neo selection cassette, and resulting offspring were crossed to remove the Flp-expressing transgene. TIN2DC-cond mice were bred to C57BL/6J mice for at least 3 generations. Upon arrival at The Jackson Laboratory, mutant mice were bred to C57BL/6J mice (Stock No. 000664) for at least one generation to establish the colony. The Tyrc-2J allele has been bred out of this strain.
Allele Name | targeted mutation 2.1, Titia de Lange |
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Allele Type | Targeted (Conditional ready (e.g. floxed), Humanized sequence, No functional change) |
Allele Synonym(s) | TIN2DC-cond; TIN2-K267E-neo |
Gene Symbol and Name | Tinf2, Terf1 (TRF1)-interacting nuclear factor 2 |
Gene Synonym(s) | |
Strain of Origin | B6(Cg)-Tyrc-2J/J |
Chromosome | 14 |
Molecular Note | A targeting construct was designed to insert a loxP-flanked transcriptional STOP cassette (Puro-4x polyA) between exons 2 and 3, and an FRT-flanked neomycin (neo) resistance cassette downstream of exon 7 of the gene. A mutation was introduced in amino acid 267 in exon 6, corresponding to human amino acid 280, resulting in a lysine-to-glutamate mutation, (K267E) commonly found in patients with dyskeratosis congenital (DC). Mutant mice were bred with Tg(ACTFLPe)9205Dym mice (on a C57BL/6 congenic background (N10)) to remove the neo selection cassette. |
When maintaining a live colony, heterozygous mice may be bred to wildtype mice from the colony or to C57BL/6J mice (Stock No. 000664) inbred mice. Homozygotes are not viable.
When using the TIN2DC-cond mouse strain in a publication, please cite the originating article(s) and include JAX stock #024859 in your Materials and Methods section.
Facility Barrier Level Descriptions
Service/Product | Description | Price |
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Heterozygous or wildtype for Tinf2<tm2.1Tdl> |
Frozen Mouse Embryo | B6(Cg)-Tinf2<tm2.1Tdl>/J | $2595.00 |
Frozen Mouse Embryo | B6(Cg)-Tinf2<tm2.1Tdl>/J | $2595.00 |
Frozen Mouse Embryo | B6(Cg)-Tinf2<tm2.1Tdl>/J | $3373.50 |
Frozen Mouse Embryo | B6(Cg)-Tinf2<tm2.1Tdl>/J | $3373.50 |
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