A Spectrum of Severe Familial Liver Disorders Associate with Telomerase Mutations

Abstract

BackgroundTelomerase 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.Methodology/Principal FindingsSixty-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.Conclusions/SignificanceThese 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.

The Promoter of Human Telomerase Reverse Transcriptase Is Activated During Liver Regeneration and Hepatocyte Proliferation

“…Interestingly, hepatic syndromes have been associated with hTERT mutations in patients with dyskeratosis congenita. 38 Moreover, two independent studies have revealed experimental evidence that hTERT mutations occur in 3-6% of cirrhosis patients with chronic liver disease (Hartmann et al and Callado et al, Hepatology in press).…”

Short Telomeres, Telomeropathy, and Subclinical Extrapulmonary Organ Damage in Patients With Interstitial Lung Disease

“…3,10,11 However, the extent of subclinical bone marrow and/or liver disease in patients with ILD and short telomeres has not been previously investigated.…”

“…10 To investigate the degree of associated marrow dysfunction, patients with short telomeres underwent a bone marrow biopsy. Among the 15 patients with short telomeres, 13 (87%) underwent a bone marrow biopsy, and two patients were still completing their lung transplant evaluations at the time of manuscript preparation.…”

Telomere in Aging and Age-Related Diseases

“…(195) Around 8-20% of familial cases of IPF were in responsible of TERC and TERT inherited mutation (196), while 37% of familial cases and 25% of sporadic cases were correlated with shorter telomeres compared to the 10th percentile of the general population, besides as-yet undiscovered genetic or environmental causes (197). Other adult-onset manifestations of impaired telomere maintenance include familial liver cirrhosis (198), aplastic anemia in adulthood (199), and sporadic acute myelogenous leukemia (AML), in which both somatic and germline mutations have been found (200).…”