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.

Keywords: Genomic instability; HGPS pathology; HGPS treatment; Laminopathies; Nuclear lamina; Progerin.

Figure 1. Abnormal processing of lamin A in HGPS

(A) Mature lamin A is produced from prelamin A, which is farnesylated followed by trimming and methylation at the C-terminus. Finally, cleavage by the Zmpste24 protease between amino acid residues 646-647 removes the farnesylated C-terminal end. (B) In HGPS patients, a mutation in exon 11 activates a cryptic splice site leading to deletion of 50 amino acid residues from the precursor protein, including the final Zmpste24 cleavage site, and accumulation of farnesylated progerin. (C) Overview of cellular consequences of progerin expression as well as proteins, small compounds and processes that influence progerin levels and/or progerin-induced defects.

Figure 2. Expression of progerin alters nuclear organization and genome stability

Cells from HGPS patients are characterized by a series of alterations including reduced expression of extracellular matrix (ECM) components, nuclear envelope blebs, clustering of nuclear pore complexes (NPC), loss of peripheral heterochromatin, and reorganized microtubules. Progerin expression also affects dynamics of nuclear envelope transmembrane proteins (NETs), including emerin, and their interactions with chromatin-associated proteins, such as BAF, transcription factors (TF) and chromatin modifiers. HGPS cells have higher levels of reactive oxygen species (ROS) and DNA damage, whereas LAP2α is downregulated.

Figure 3. Nuclear defects in HGPS cells

Immunofluorescence performed in primary normal human fibroblasts (NF) and HGPS patient derived fibroblasts (HGPS) with antibodies recognizing lamin A (green, top panels), histone modification H3K9me3 (red, medium panels), and γH2AX (yellow, bottom panels), a marker of DNA damage. DAPI staining was used to demarcate nuclei (blue staining in all panels). Note how HGPS patient derived fibroblasts exhibit nuclear morphological abnormalities, decreased levels of H3K9me3, and accumulation of basal levels of unrepaired DNA damage, when compared to normal fibroblasts.

Figure 4. Pathophysiology of HGPS

Scheme shows the prominent symptoms and signs of HGPS, as well as potential treatments to test in the future to ameliorate the pathophysiology of this devastating disease.