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.
