Chronic lung disease is the third leading cause of death in the United States.Emphysema and pulmonary fibrosis are two of the most common forms and are thought in part to represent a premature aging phenotype in the lung. This thesis aims to define the role of telomeres in the genetics of age-related lung disease.Using publically available sequencing data from patients with severe, early-onset COPD, we identified telomerase mutations as a novel Mendelian genetic cause of emphysema.The patients in this cohort showed a unique gene-environment interaction in which smoking was necessary for development of the emphysema phenotype, and female telomerase mutation carriers were particularly prone to developing emphysema.In a family with pulmonary fibrosis and idiopathic infertility we demonstrated a case of functional reversion in the proband, who carried both a germline dominant negative missense allele in the telomere binding protein TINF2 and an acquired somatic deletion in cis that abolished expression of the missense allele in bone marrow-derived cells.In the final chapter, we identify mutations in the RNA biogenesis protein NAF1 as a cause of autosomal dominant familial pulmonary fibrosis-emphysema.The mutations segregated with the disease phenotype and short telomeres and disrupted nuclear targeting of NAF1.Taken together, these genetic findings have immediate clinical implications in the lung transplant setting, as patients with short telomeres are especially sensitive to myelosuppresive regimens.They also point to telomere-mediated senescence as a key mechanism of age-related lung disease pathogenesis.
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Genetics and mechanisms of telomere-mediated lung disease
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