A number sign (#) is used with this entry because of evidence that telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-8 (PFBMFT8) is caused by heterozygous mutation in the POT1 gene (606478) on chromosome 7q31. One such family has been reported.

Telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-8 (PFBMFT8) is an autosomal dominant disorder characterized by the onset of progressive pulmonary fibrosis in adulthood. Some affected individuals have signs of bone marrow failure, such as thrombocytopenia, or liver dysfunction, including hepatopulmonary syndrome. Other features of dyskeratosis congenita, including premature graying of the hair, may be observed. Telomeres are shortened compared to controls (Kelich et al., 2022).

For a discussion of genetic heterogeneity of telomere-related pulmonary fibrosis and/or bone marrow failure, see PFBMFT1 (614742).

Kelich et al. (2022) reported a family in which 4 males spanning 3 generations had pulmonary fibrosis. The proband was a 32-year-old man with interstitial lung disease, pulmonary fibrosis, and digital clubbing. He also had significant liver disease with nodular regenerative hyperplasia, portal hypertension with esophageal varices and splenomegaly, and hepatopulmonary syndrome. He had a liver transplant at age 35 and a lung transplant 2 years later. Thrombocytopenia was also noted. His affected father, who was a smoker, had dyspnea, peritoneal fibrosis, and progressive pulmonary fibrosis. The paternal grandfather was reportedly affected. A father and son in another branch of the family also had pulmonary fibrosis. In addition, this father had premature graying of the hair, thrombocytopenia, and a history of liver abnormalities with fibrosing cholecystitis and cholecystectomy. All patients had shortened telomeres.

The transmission pattern of PFBMFT8 in the family reported by Kelich et al. (2022) was consistent with autosomal dominant inheritance. Genetic anticipation was observed in the family.

In 4 affected members of a family with PFBMFT8, Kelich et al. (2022) identified a heterozygous missense mutation in the POT1 gene (L259S; 606478.0012). The mutation, which was found by next-generation panel sequencing, segregated with the disorder in the family and was not present in the gnomAD database. In vitro functional expression studies showed that the mutant protein had decreased DNA binding affinity compared to wildtype, although it was able to interact with TPP1 (ACD; 609377) and localize to telomeres. Nuclear localization was reduced, suggesting that less POT1 is bound to DNA. Although the patients were noted to have short telomeres, the mutant protein did not negatively affect telomerase extension activity in vitro. Patient fibroblasts harboring the mutation had shortened lagging strands during synthesis, an increase in the telomeric overhang signal, and sister telomere loss during metaphase. The L259S mutation led to an increase in telomere dysfunction-induced foci in patient cells, suggesting a defect in telomere capping that could lead to shortened telomeres. Finally, the L259S mutation induced premature cellular senescence in patient cells, likely a consequence of telomere-induced DNA damage resulting from the mutation. Of note, HEK293 cells expressing the mutation in vitro developed longer telomeres compared to wildtype, suggesting that mutant POT1 is defective in limiting telomere elongation in cells.