A Spectrum of Severe Familial Liver Disorders Associate with Telomerase Mutations
Open Access
- 20 November 2009
- journal article
- case report
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 4 (11), e7926
- https://doi.org/10.1371/journal.pone.0007926
Abstract
Telomerase is an enzyme specialized in maintaining telomere lengths in highly proliferative cells. Loss-of-function mutations cause critical telomere shortening and are associated with the bone marrow failure syndromes dyskeratosis congenita and aplastic anemia and with idiopathic pulmonary fibrosis. Here, we sought to determine the spectrum of clinical manifestations associated with telomerase loss-of-function mutations. Sixty-nine individuals from five unrelated families with a variety of hematologic, hepatic, and autoimmune disorders were screened for telomerase complex gene mutations; leukocyte telomere length was measured by flow fluorescence in situ hybridization in mutation carriers and some non-carriers; the effects of the identified mutations on telomerase activity were determined; and genetic and clinical data were correlated. In six generations of a large family, a loss-of-function mutation in the telomerase enzyme gene TERT associated with severe telomere shortening and a range of hematologic manifestations, from macrocytosis to acute myeloid leukemia, with severe liver diseases marked by fibrosis and inflammation, and one case of idiopathic pulmonary fibrosis but not with autoimmune disorders. Additionally, we identified four unrelated families in which loss-of-function TERC or TERT gene mutations tracked with marrow failure, pulmonary fibrosis, and a spectrum of liver disorders. These results indicate that heterozygous telomerase loss-of-function mutations associate with but are not determinant of a large spectrum of hematologic and liver abnormalities, with the latter sometimes occurring in the absence of marrow failure. Our findings, along with the link between pulmonary fibrosis and telomerase mutations, also suggest a common pathogenic mechanism for fibrotic diseases in which defective telomere repair plays important role.Keywords
This publication has 34 references indexed in Scilit:
- Genetic variation in telomere maintenance genes, telomere length, and lung cancer susceptibilityLung Cancer, 2009
- Cancer in dyskeratosis congenitaBlood, 2009
- Familial idiopathic pulmonary fibrosis in association with bone marrow hypoplasia and hepatic nodular regenerative hyperplasia: a new "trimorphic" syndromeThorax, 2009
- Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemiaProceedings of the National Academy of Sciences of the United States of America, 2009
- Common 5p15.33 and 6p21.33 variants influence lung cancer riskNature Genetics, 2008
- Lung cancer susceptibility locus at 5p15.33Nature Genetics, 2008
- The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenitaNature, 2001
- Switching and Signaling at the TelomereCell, 2001
- Dyskeratosis congenita in all its formsBritish Journal of Haematology, 2000
- Inhibition of Experimental Liver Cirrhosis in Mice by Telomerase Gene DeliveryScience, 2000