title: Accelerated telomere shortening and replicative senescence in human fibroblasts overexpressing mutant and wild-type lamin A.
abstract: LMNA mutations are responsible for a variety of genetic disorders, including muscular dystrophy, lipodystrophy, and certain progeroid syndromes, notably Hutchinson-Gilford Progeria. Although a number of clinical features of these disorders are suggestive of accelerated aging, it is not known whether cells derived from these patients exhibit cellular phenotypes associated with accelerated aging. We examined a series of isogenic skin fibroblast lines transfected with LMNA constructs bearing known pathogenic point mutations or deletion mutations found in progeroid syndromes. Fibroblasts overexpressing mutant lamin A exhibited accelerated rates of loss of telomeres and shortened replicative lifespans, in addition to abnormal nuclear morphology. To our surprise, these abnormalities were also observed in lines overexpressing wild-type lamin A. Copy number variants are common in human populations; those involving LMNA, whether arising meiotically or mitotically, might lead to progeroid phenotypes. In an initial pilot study of 23 progeroid cases without detectable WRN or LMNA mutations, however, no cases of altered LMNA copy number were detected. Nevertheless, our findings raise a hypothesis that changes in lamina organization may cause accelerated telomere attrition, with different kinetics for overexpession of wild-type and mutant lamin A, which leads to rapid replicative senescence and progroid phenotypes.
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Shurong
authors.initials: S
authors.lastname: Huang
authors.forename: Rosa Ana
authors.initials: RA
authors.lastname: Risques
authors.forename: George M
authors.initials: GM
authors.lastname: Martin
authors.forename: Peter S
authors.initials: PS
authors.lastname: Rabinovitch
authors.forename: Junko
authors.initials: J
authors.lastname: Oshima
mesh_terms: D002455:Cell Division / Q000235:genetics; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D018628:Gene Dosage / Q000235:genetics; D006801:Humans; D034904:Lamin Type A / Q000096:biosynthesis / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011371:Progeria / Q000235:genetics*; D016615:Telomere / Q000235:genetics*; D014162:Transfection
chemical_list: D034904:Lamin Type A