期刊
EXPERIMENTAL CELL RESEARCH
卷 314, 期 1, 页码 82-91出版社
ELSEVIER INC
DOI: 10.1016/j.yexcr.2007.08.004
关键词
lamin; laminopathies; progeroid syndromes; Hutchison-Gilford Progeroid; syndrome; aging
资金
- NCI NIH HHS [R24 CA078088-10, R24 CA078088, CA78088] Funding Source: Medline
- NIA NIH HHS [P30 AG013280, AG13280] Funding Source: Medline
- NICHD NIH HHS [R21 HD044782, HD44782] Funding Source: Medline
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT [R21HD044782] Funding Source: NIH RePORTER
- NATIONAL CANCER INSTITUTE [R24CA078088] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P30AG013280] Funding Source: NIH RePORTER
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 wildtype and mutant lamin A, which leads to rapid replicative senescence and progroid phenotypes. Published by Elsevier Inc.
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