Mice carrying the homologous human shelterin POT1-L259S mutation linked to pulmonary fibrosis show a telomerase deficiency-like phenotype with telomere shortening with increasing mouse generations

Pulmonary fibrosis is a lethal disease associated with damaging insults to the lung and with organismal aging. The presence of short and dysfunctional telomeres has been placed at the origin of this disease in a percentage of both familial and sporadic cases. Recently, a mutation in the telomere-binding protein protection of telomeres 1 in humans (hPOT1), the hPOT1 L259S mutation, was found in families with idiopathic pulmonary fibrosis. Here, we generated a Pot1a L261S knock-in mouse harboring the murine homologous hPOT1 L259S mutation. We found that the homozygous Pot1a L261S mice show shorter telomeres and degenerative pathologies in the intestine, testes, and lungs at old ages, a phenotype that is aggravated with increasing mouse generations, in striking analogy to the telomerase-deficient mouse models. Furthermore, we found that the POT1a-L261S mutant protein binds more strongly to TPP1 and to telomerase and impedes telomerase-dependent telomere lengthening in vivo. We show that telomerase activity at telomeres is reduced in the presence of POT1a-L261S, which behaves as a dominant negative mutant, thus providing a potential mechanism by which Pot1a L261S knock-in mice phenocopy the short telomere phenotype of the telomerase knockout model.