Journal Article

A Spectrum of Severe Familial Liver Disorders Associate with Telomerase Mutations

Young, Neal S., Lansdorp, Peter M., Regal, Joshua A., Kleiner, David E., Peterson, Nathan R., Chanock, Stephen J., Calado, Rodrigo T., Schrump, David S., Pons, Veronica

2009

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Abnormalities / Acute myeloid leukemia / Adolescent / Adult / Aged / Aged, 80 and over / Anemia / Anemia, Aplastic - diagnosis / Anemia, Aplastic - genetics / Aplastic anemia / Autoimmune diseases / Blood diseases / Bone marrow / Bone Marrow - pathology / Carriers / Cell division / Child / Chromosomes / Disorders / DNA Mutational Analysis / Dyskeratosis / Dyskeratosis Congenita - diagnosis / Dyskeratosis Congenita - genetics / Enzymes / Failure / Female / Fibrosis / Fluorescence / Fluorescence in situ hybridization / Gastroenterology and Hepatology/Hepatology / Gene mutation / Genes / Genetic aspects / Genetics and Genomics/Cancer Genetics / Genetics and Genomics/Genetics of Disease / Genetics and Genomics/Medical Genetics / Heart / Hematology / Hematology/Acute Myeloid Leukemia / Hematology/Myelodysplastic Syndrome and Bone Marrow Failure / Heterozygote / Humans / Idiopathic Pulmonary Fibrosis - diagnosis / Idiopathic Pulmonary Fibrosis - genetics / Leukemia / Liver / Liver - abnormalities / Liver diseases / Liver Diseases - diagnosis / Liver Diseases - genetics / Lung cancer / Lung diseases / Male / Middle Aged / Mutation / Myeloid leukemia / Oncology/Hematological Malignancies / Patients / Pulmonary fibrosis / Respiratory Medicine/Interstitial Lung Diseases / Respiratory tract diseases / Senescence / Telomerase / Telomerase - genetics / Telomeres