A Spectrum of Severe Familial Liver Disorders Associate with Telomerase Mutations

摘要: Background Telomerase is an enzyme specialized in maintaining telomere lengths highly proliferative cells. Loss-of-function mutations cause critical shortening and are associated with the bone marrow failure syndromes dyskeratosis congenita aplastic anemia idiopathic pulmonary fibrosis. Here, we sought to determine spectrum of clinical manifestations telomerase loss-of-function mutations. Methodology/Principal Findings Sixty-nine individuals from five unrelated families a variety hematologic, hepatic, autoimmune disorders were screened for complex gene mutations; leukocyte length was measured by flow fluorescence situ hybridization mutation carriers some non-carriers; effects identified on activity determined; genetic data correlated. In six generations large family, TERT severe range hematologic manifestations, macrocytosis acute myeloid leukemia, liver diseases marked fibrosis inflammation, one case but not disorders. Additionally, four which TERC or tracked failure, fibrosis, disorders. Conclusions/Significance These results indicate that heterozygous associate determinant abnormalities, latter sometimes occurring absence failure. Our findings, along link between mutations, also suggest common pathogenic mechanism fibrotic defective repair plays important role.