Accelerated telomere shortening and replicative senescence in human fibroblasts overexpressing mutant and wild-type lamin A

• Published in: Experimental cell research Vol. 314; no. 1; pp. 82 - 91
• Main Authors: Huang, Shurong, Risques, Rosa Ana, Martin, George M., Rabinovitch, Peter S., Oshima, Junko
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2008; Elsevier BV
• Subjects: 60 APPLIED LIFE SCIENCES; AGING; Cell Division - genetics; Cell Line, Transformed; Cell Proliferation; Cellular biology; Cellular Senescence - genetics; DNA Replication - genetics; FIBROBLASTS; Fibroblasts - cytology; Fibroblasts - metabolism; Gene Dosage - genetics; GENE MUTATIONS; Genetic disorders; Genotype & phenotype; Humans; Hutchison-Gilford Progeroid Syndrome; Lamin; Lamin Type A - biosynthesis; Lamin Type A - genetics; Laminopathies; MORPHOLOGY; MUTANTS; Mutation; Mutation - genetics; PATIENTS; PHENOTYPE; Progeria - genetics; Progeroid syndromes; SKIN; Telomere - genetics; TELOMERES; Transfection; Aging; Lamin; Laminopathies; Hutchison-Gilford Progeroid Syndrome; Progeroid syndromes
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2007.08.004

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.