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.

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

“…The animals were born with Mendelian ratio and were completely normal at birth. However, within 1 month they appeared smaller than their wild‐type/non‐Tg (WT) littermates (Figure 1c), and within 2 months they displayed a severe phenotype (Figure 1c and Table 1) that was reminiscent of segmental forms of human progerias (Gonzalo, Kreienkamp, & Askjaer, 2017; Karikkineth, Scheibye‐Knudsen, Fivenson, Croteau, & Bohr, 2017; Liao & Kennedy, 2014; Pivnick et al, 2000). Indeed, they remained smaller throughout their entire lifespan (Figure 1d), appeared phenotypically old (Figure 1c), and displayed a very short lifespan (Figure 1e).…”

“…At birth, patients are typically smaller and display facial dysmorphism; as they grow, they develop a complex phenotype that often mimics accelerated forms of pathogenic aging. Segmental progerias include Hutchinson–Gilford, Cokayne, Werner, Bloom, and Rothmund–Thompsons syndromes, among others (Gonzalo et al, 2017; Karikkineth et al, 2017; Kubben & Misteli, 2017; Swahari & Nakamura, 2016). …”

Disruption of PCNA-lamins A/C interactions by prelamin A induces DNA replication fork stalling

“…Lamins A and C are both derived from the same gene ( LMNA ), however lamin A is extensively post-translationally modified to become mature lamin A. 2,3 Defective processing can lead to the accumulation of lamin A precursors such as progerin 4 and prelamin A 5 that are implicated in laminopathies Hutchinson-Gilford progeria syndrome 6 and restrictive dermopathy 5 respectively. Despite inducing comparable effects upon cells, progerin and prelamin A differ structurally and biochemically, with progerin being a truncated form of lamin A missing 50 internal amino acids whereas prelamin A is the full transcript from the LMNA gene 7 .…”

A novel somatic mutation achieves partial rescue in a child with Hutchinson-Gilford progeria syndrome

“…Progerin mRNA is transcribed from the classic HGPS allele around 80% of the time, from intron 11 splice donor mutations at varying rates depending on how severely the mutation interferes with the 5′ splice site consensus G/GTRAGT sequence,5 and from a normal LMNA gene less than 2% of the time,6 but this isoform is produced in greater abundance as normal cells approach senescence 6. Progerin expression drives nuclear morphological abnormalities, mitochondrial dysfunction, defects in DNA repair, premature senescence7 and a variety of epigenetic alterations including global chromatin changes and misregulated gene expression 8. There are two documented sibling occurrences, both presumably stemming from parental mosaicism, where one phenotypically normal parent has germline mosaicism for cells with the classic HGPS mutation (c. 1824 G>T; p.G608G) 9…”