title: A spectrum of severe familial liver disorders associate with telomerase mutations.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America. calador@nhlbi.nih.gov
authors: Rodrigo T
authors: RT
authors: Calado
authors: Joshua A
authors: JA
authors: Regal
authors: David E
authors: DE
authors: Kleiner
authors: David S
authors: DS
authors: Schrump
authors: Nathan R
authors: NR
authors: Peterson
authors: Veronica
authors: V
authors: Pons
authors: Stephen J
authors: SJ
authors: Chanock
authors: Peter M
authors: PM
authors: Lansdorp
authors: Neal S
authors: NS
authors: Young
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000741:Anemia, Aplastic / Q000175:diagnosis / Q000235:genetics; D001853:Bone Marrow / Q000473:pathology; D002648:Child; D004252:DNA Mutational Analysis; D019871:Dyskeratosis Congenita / Q000175:diagnosis / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000175:diagnosis / Q000235:genetics; D008099:Liver / Q000002:abnormalities; D008107:Liver Diseases / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019098:Telomerase / Q000235:genetics*
chemical_list: D019098:Telomerase