Despite their frequency and severe impact on children in the TBD community, mutations in the gene TINF2 remain some of the least understood causes of telomere biology disorders (TBDs).

Significantly, one central question related to how these mutations cause disease might just have been answered. The TINF2 gene provides the information cells need to make the telomere-binding protein TIN2. Mutations in TINF2 that are associated with TBDs have certain recurring features. First, each of us carries two copies of TINF2 – one inherited from our mother and the other from our father. Nonetheless, when a TINF2 mutation is found in a patient with a TBD, it is usually not found in one of their parents; thus, the mutation is classified as de novo (or new). In addition, TBD-causing TINF2 mutations cluster in a small and specific region of the gene, suggesting that the mutations affect the TIN2 protein in a particular way. Lastly, the impact of these de novo TINF2 mutations is often profound, resulting in very short telomeres and many TBD-related conditions in childhood. This contrasts, for example, with what is typically observed in multi-generation families with a mutation in one copy of the TERT gene, where the impact is progressive, starting with disease presentations in older adults in the earlier generations. Together, these features led us to wonder why the normal copy of TINF2 in patients with TINF2-associated TBDs appears incapable of supporting telomere length.

In a collaborative effort, we recently published a potential answer to this question in the journal Blood. We started with cells that carried a TINF2-TBD mutation and, as expected, had very short telomeres. We then deleted this mutated copy and found that the telomeres became longer and reset to a length characteristic of cells without a TINF2-TBD mutation. From this, we learned that an intact copy of the TINF2 gene is fully capable of doing its job at the telomere but that the mutant copy of the TINF2 gene functions as a “molecular poison” that overrides telomere length control and forces telomeres to become short. This initial finding was made in cells that were not directly taken from a patient but that we genetically engineered to have a TINF2-TBD mutation. Yet, the results suggested that strategies targeting the TINF2 gene that carries the TBD mutation could restore telomere function in patient cells. As a first step towards this, we showed that the strategy to remove the disease mutation could work in patient blood cells, which are often severely impacted in TINF2-associated TBDs.

However, we did not yet show that this intervention restores the cells’ telomere length. Thus, future experiments and safety studies are needed to evaluate whether these findings can be translated to patients.