Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome
| Autor: | Robert D. Goldman, Michael R. Erdos, Renee Varga, Francis S. Collins, Maria Eriksson, Dale K. Shumaker, Satya Khuon, Leslie B. Gordon, Melissa G. Mendez, Yosef Gruenbaum, Anne E. Goldman |
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| Rok vydání: | 2004 |
| Předmět: |
Premature aging
congenital hereditary and neonatal diseases and abnormalities Aging Nuclear Envelope Mitosis Laminopathy Biology LMNA Progeria medicine Humans Cellular Senescence Aged Sequence Deletion Genetics Aged 80 and over Cell Nucleus Multidisciplinary integumentary system Cell Cycle nutritional and metabolic diseases Infant Fibroblasts Biological Sciences medicine.disease Progerin Lamin Type A Cell Nucleus Structures Cell biology Cell nucleus medicine.anatomical_structure Nuclear lamina Female Lamin |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 101(24) |
| ISSN: | 0027-8424 |
| Popis: | Hutchinson–Gilford progeria syndrome (HGPS) is a premature aging disorder, commonly caused by a point mutation in the lamin A gene that results in a protein lacking 50 aa near the C terminus, denoted LAΔ50. Here we show by light and electron microscopy that HGPS is associated with significant changes in nuclear shape, including lobulation of the nuclear envelope, thickening of the nuclear lamina, loss of peripheral heterochromatin, and clustering of nuclear pores. These structural defects worsen as HGPS cells age in culture, and their severity correlates with an apparent increase in LAΔ50. Introduction of LAΔ50 into normal cells by transfection or protein injection induces the same changes. We hypothesize that these alterations in nuclear structure are due to a concentration-dependent dominant-negative effect of LAΔ50, leading to the disruption of lamin-related functions ranging from the maintenance of nuclear shape to regulation of gene expression and DNA replication. |
| Databáze: | OpenAIRE |
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