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 <i>protection of telomeres 1</i> in humans (<i>hPOT1</i>), the <i>hPOT1-L259S</i> mutation, was found in families with idiopathic pulmonary fibrosis. Here, we generated a <i>Pot1a</i> ^<i>L261S</i> knock-in mouse harboring the murine homologous <i>hPOT1-L259S</i> mutation. We found that the homozygous <i>Pot1a</i> ^<i>L261S</i> 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 <i>Pot1a</i> ^<i>L261S</i> knock-in mice phenocopy the short telomere phenotype of the telomerase knockout model.