Robert D. Goldman1, Dale K. Shumaker1, Michael R. Erdos1, Maria Eriksson1, Anne E. Goldman1, Leslie B. Gordon1,2, Yosef Gruenbaum1, Satya Khuon1, Melissa G. Mendez1, Renée Varga1, Francis S. Collins1
1Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL 60611; Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, 50 South Drive, MSC 8004, Bethesda, MD 20892-8004; Department of Medical Nutrition, Karolinska Institutet, Novum, Halsovagen 7, Hiss E, Plan 6, 141 57 Huddinge, Sweden; Department of Anatomy and Cellular Biology, Tufts University School of Medicine, 136 Harrison...
2Rhode Island Hospital
Tóm tắt
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.
