title: Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations.
abstract: Products of the LMNA gene, primarily lamin A and C, are key components of the nuclear lamina, a proteinaceous meshwork that underlies the inner nuclear membrane and is essential for proper nuclear architecture. Alterations in lamin A and C that disrupt the integrity of the nuclear lamina affect a whole repertoire of nuclear functions, causing cellular decline. In humans, hundreds of mutations in the LMNA gene have been identified and correlated with over a dozen degenerative disorders, referred to as laminopathies. These diseases include neuropathies, muscular dystrophies, lipodystrophies, and premature aging diseases. This review focuses on one of the most severe laminopathies, Hutchinson-Gilford Progeria Syndrome (HGPS), which is caused by aberrant splicing of the LMNA gene and expression of a mutant product called progerin. Here, we discuss current views about the molecular mechanisms that contribute to the pathophysiology of this devastating disease, as well as the strategies being tested in vitro and in vivo to counteract progerin toxicity. In particular, progerin accumulation elicits nuclear morphological abnormalities, misregulated gene expression, defects in DNA repair, telomere shortening, and genomic instability, all of which limit cellular proliferative capacity. In patients harboring this mutation, a severe premature aging disease develops during childhood. Interestingly, progerin is also produced in senescent cells and cells from old individuals, suggesting that progerin accumulation might be a factor in physiological aging. Deciphering the molecular mechanisms whereby progerin expression leads to HGPS is an emergent area of research, which could bring us closer to understanding the pathology of aging.
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA. Electronic address: sgonzalo@slu.edu.
authors.forename: Susana
authors.initials: S
authors.lastname: Gonzalo
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
authors.forename: Ray
authors.initials: R
authors.lastname: Kreienkamp
authors.affiliation: Andalusian Center for Developmental Biology (CABD), CSIC/Junta de Andalucia/Universidad Pablo de Olavide, Carretera de Utrera, Km 1, 41013 Seville, Spain.
authors.forename: Peter
authors.initials: P
authors.lastname: Askjaer
mesh_terms: D000375:Aging / Q000502:physiology*; D019588:Aging, Premature / Q000235:genetics*; D016922:Cellular Senescence / Q000502:physiology; D004260:DNA Repair; D019468:Disease Management; D042822:Genomic Instability; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D009154:Mutation; D011371:Progeria / Q000235:genetics / Q000503:physiopathology
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A
keywords: Genomic instability; HGPS pathology; HGPS treatment; Laminopathies; Nuclear lamina; Progerin