HGPS (Hutchinson–Gilford progeria syndrome) is a severe childhood disorder that appears to mimic an accelerated aging process. The disease is most commonly caused by gene mutations that disrupt the normal post-translational processing of lamin A, a structural component of the nuclear envelope. Impaired processing results in aberrant retention of a farnesyl group at the C-terminus of lamin A, leading to altered membrane dynamics. It has been widely proposed that persistence of the farnesyl moiety is the major factor responsible for the disease, prompting clinical trials of farnesyltransferase inhibitors to prevent lamin A farnesylation in children afflicted with HGPS. Although there is evidence implicating farnesylation in causing some of the cellular defects of HGPS, results of several recent studies suggest that aberrant lamin A farnesylation is not the only determinant of the disease. These findings have important implications for the design of treatments for this devastating disease.

Introduction

HGPS (Hutchinson–Gilford progeria syndrome) is a rare inherited disorder with features reminiscent of premature aging. A detailed description of the phenotype has been made elsewhere [1]. In brief, affected children appear normal at birth, but begin to show symptoms by 1 year of age. Early symptoms are failure to thrive, sclerodermatous skin and loss of subcutaneous fat. They go on to progressively develop the typical progeroid phenotype of impaired growth, alopecia, lipodystrophy, joint stiffness, osteolysis and distinctive facial features including prominent forehead and eyes, glyphic nose and micrognathia, giving the overall appearance of an aged person. Premature atherosclerosis leads to death from cardiovascular or cerebrovascular disease, at a median age of 13 years.

HGPS is one of several disorders, termed laminopathies, caused by mutations in the LMNA gene, which encodes lamin A and C (reviewed in [2]). Rare cases of HGPS and related progeroid syndromes can also result from mutation of the ZMPSTE24 gene [35]. LMNA comprises 12 exons and undergoes alternative splicing at its 3′ end to produce several transcripts encoding the A-type lamins, the major forms being lamins A and C. On the other hand, ZMPSTE24 encodes a zinc metalloproteinase involved in the post-translational processing of lamin A. Lamins are components of the nuclear lamina, a fibrous network of proteins that underlies the inner nuclear membrane. The lamina provides structural support to the nucleus as well as binding to inner nuclear membrane and nucleoplasmic proteins. Lamins and their binding partners play a key role in many nuclear functions including chromatin organization, DNA replication, gene transcription and nuclear–cytoskeletal connection (reviewed in [6,7]).

Lamins A and C differ only at their C-termini: the proteins are identical up to residue 566; lamin C then has a further six unique residues, whereas lamin A has 90 additional residues encoded by exons 11 and 12 of the LMNA gene. Lamin A is produced as a precursor, pre-lamin A, which undergoes post-translational modification involving farnesylation of a CaaX (where a is an aliphatic residue) membrane-targeting motif at the extreme C-terminus. This process has been described extensively elsewhere (e.g. [79]) and so will be only briefly described here. Processing of pre-lamin A is a four-step process mediated in part by the zinc metalloproteinase ZMPSTE24. First, the cysteine residue in the CaaX motif is farnesylated, then the aaX tripeptide is cleaved and released, either by ZMPSTE24 or by RCE1 (Ras-converting enzyme 1). Next, the exposed farnesylated cysteine residue is methylated and a second cleavage by ZMPSTE24 releases a further 15 amino acids, including the methylated farnesylcysteine residue. Thus lamin A is only transiently farnesylated. This is in contrast with the other lamin isoforms which either are not farnesylated at all (lamin C) or remain permanently farnesylated (B-type lamins). It is currently not known why lamin A undergoes this initial farnesylation, but it may reflect a requirement for membrane-targeting of newly synthesized lamin A. Nevertheless, defects in this process clearly underpin the molecular basis of HGPS.

In up to 80% of cases, HGPS is caused by a de novo, heterozygous, C>T nucleotide substitution at codon 608 (GGC>GGT) of LMNA, referred to as G608G [10,11]. Although apparently a silent mutation, it partially activates a cryptic splice donor site in exon 11, resulting in a 50-amino-acid internal deletion near the C-terminus of lamin A, whereas lamin C is unaffected. The truncated lamin A protein lacks the second ZMPSTE24 cleavage site and hence cannot be fully post-translationally processed (Figure 1). As a result, a permanently farnesylated and truncated form of lamin A persists, which has severe dominant-negative effects on the cell (see below). This mutant protein is usually referred to as progerin or LAΔ50.

Schematic representation of the pre-lamin A processing pathway in normal and disease states

Figure 1
Schematic representation of the pre-lamin A processing pathway in normal and disease states

The amino acid sequence involved in processing is shown at the C-terminus. (A) Processing of wild-type lamin A. The region highlighted in grey is deleted in progerin. Mutations in ZMPSTE24 impair or abolish the final cleavage step. (B) Processing of progerin, produced by activation of a cryptic splice site within exon 11 of the LMNA gene that deletes residues 607–656, including the second ZMPSTE24 cleavage site. In both cases, the gene defects result in persistence of the farnesylated lamin A intermediate.

Figure 1
Schematic representation of the pre-lamin A processing pathway in normal and disease states

The amino acid sequence involved in processing is shown at the C-terminus. (A) Processing of wild-type lamin A. The region highlighted in grey is deleted in progerin. Mutations in ZMPSTE24 impair or abolish the final cleavage step. (B) Processing of progerin, produced by activation of a cryptic splice site within exon 11 of the LMNA gene that deletes residues 607–656, including the second ZMPSTE24 cleavage site. In both cases, the gene defects result in persistence of the farnesylated lamin A intermediate.

HGPS cells exhibit profound defects in nuclear morphology

Figure 2
HGPS cells exhibit profound defects in nuclear morphology

Control and HGPS fibroblasts were imaged by immunofluorescence microscopy following staining with anti-(lamin A/C) antibodies. Whereas control nuclei are ovoid with uniform lamin A/C staining, HGPS nuclei are highly lobulated, with membrane folds and uneven lamin A/C staining.

Figure 2
HGPS cells exhibit profound defects in nuclear morphology

Control and HGPS fibroblasts were imaged by immunofluorescence microscopy following staining with anti-(lamin A/C) antibodies. Whereas control nuclei are ovoid with uniform lamin A/C staining, HGPS nuclei are highly lobulated, with membrane folds and uneven lamin A/C staining.

Genotype–phenotype correlations

Progeroid disorders can be caused by autosomal dominant or autosomal recessive mutation of the LMNA or ZMPSTE24 genes (summarized in Table 1). The typical, or classical, HGPS phenotype, caused by the dominant G608G LMNA mutation, is consistent among most patients. However, there is significant variation in disease severity among progeroid disorders caused by other LMNA or ZMPSTE24 mutations. In general, it seems that disease severity correlates with the level of aberrantly farnesylated lamin A. Several mutations cause activation of the same cryptic splice site in exon 11 of LMNA, and disease severity correlates well with the usage of this splice site. For example, V607V results in stronger activation of the splice site, producing much higher levels of progerin than in classical HGPS [12]. As a result, individuals carrying this mutation have a particularly severe form of the disease.

Table 1
Progeria-associated mutations reported in the LMNA and ZMPSTE24 genes, showing the cDNA sequence change, the consequent effect at the protein level and the associated disease severity

Inheritance is autosomal dominant (AD) or autosomal recessive (AR). fs, frameshift; MD, muscular dystrophy; RD, restrictive dermopathy.

Gene cDNA Protein Inheritance Phenotype Reference(s) 
LMNA 29C>T T10I AD Atypical combined with Seip syndrome [41
 428C>T S143F AD Atypical with myopathy [42,43
 433G>A E145K AD Atypical [11
 1411C>T R471C AR Atypical with MAD/MD [44
 1579C>T R527C AR Atypical/severe skeletal [45
 1583C>T T528M AR Classical [15
 1619T>C M540T AR Classical [15
 1626G>C K542N AR Classical [14
 1733A>T E578V AD Mild [41
 1821G>A Δ607–656 (V607V) AD Severe [12
 1824C>T Δ607–656 (G608G) AD Classical [10,11
 1822G>A Δ607–656 (G608S) AD Classical [11,46
 1868C>G Δ622–656 (T623S) AD Mild [47,48
 1930C>T R644C AD Mild [41
 1968+1G>A Δ567–656; Δ607–656* AD Severe; RD* [5,12
ZMPSTE24 794A>G N265S AR Severe [49
 1085_1086insT L362FfsX379 AR Severe [49
 1204_1225del22 V402SfsX403 AR Classical** [50
Gene cDNA Protein Inheritance Phenotype Reference(s) 
LMNA 29C>T T10I AD Atypical combined with Seip syndrome [41
 428C>T S143F AD Atypical with myopathy [42,43
 433G>A E145K AD Atypical [11
 1411C>T R471C AR Atypical with MAD/MD [44
 1579C>T R527C AR Atypical/severe skeletal [45
 1583C>T T528M AR Classical [15
 1619T>C M540T AR Classical [15
 1626G>C K542N AR Classical [14
 1733A>T E578V AD Mild [41
 1821G>A Δ607–656 (V607V) AD Severe [12
 1824C>T Δ607–656 (G608G) AD Classical [10,11
 1822G>A Δ607–656 (G608S) AD Classical [11,46
 1868C>G Δ622–656 (T623S) AD Mild [47,48
 1930C>T R644C AD Mild [41
 1968+1G>A Δ567–656; Δ607–656* AD Severe; RD* [5,12
ZMPSTE24 794A>G N265S AR Severe [49
 1085_1086insT L362FfsX379 AR Severe [49
 1204_1225del22 V402SfsX403 AR Classical** [50
*

Two independent reports show different effects on lamin A mRNA splicing in unrelated patients with this mutation, leading to different disease severity. This could be due to modifier effects in other genes.

**

Phenotype moderated by co-segregating null mutation in LMNA (R654X) that reduces the level of farnesylated pre-lamin A.

At opposite extremes of the spectrum of disease severity are two related disorders also caused by mutation of either the LMNA or ZMPSTE24 genes. The lethal neonatal laminopathy, restrictive dermopathy, lies at the most severe end of the spectrum. This disorder shares aspects of HGPS, such as growth retardation and micrognathia, but is characterized by thin tight skin causing a restriction in joint extension and fixing the mouth in an ‘O’ shape. Live-born babies usually die from respiratory failure in the first week of life. Inheritance is autosomal recessive, usually involving homozygous or compound heterozygous ZMPSTE24 mutations, the most common being L362FfsX379 [4,5]. These mutations completely abolish ZMPSTE24 activity, resulting in a total absence of mature lamin A and accumulation of high levels of farnesylated pre-lamin A [4,13]. In contrast, ZMPSTE24 mutations that lead to the milder laminopathy MAD (mandibuloacral dysplasia) result in partial ZMPSTE24 activity [3].

However, the presence of partially processed, farnesylated pre-lamin A may not be the only mechanism underlying progeria. A number of atypical HGPS patients with recessive point mutations in LMNA have been reported. Most of these mutations are not predicted to affect lamin A processing directly as they lie upstream of exon 11, with some as distant as exon 1 (Table 1). We have come across only two cases of amino acid substitutions in LMNA resulting in the classical HGPS phenotype. Homozygous K542N mutations were found in four affected siblings [14], who showed all features of typical HGPS together with additional skeletal abnormalities usually associated with MAD. Compound heterozygous T528M and M540T mutations were found in a 2-year-old HGPS patient [15]. Intriguingly, there was no build up of progerin or pre-lamin A in cells from this individual, suggesting that permanent farnesylation of lamin A may not be the cause of disease in this patient.

Multiple cellular defects in classical progeria

Many studies have now been performed on progerin-expressing cells, using either transfected cells or dermal fibroblasts isolated from classical progeria patients, all of which point to the mutant progerin having a severe dominant-negative effect on nuclear structure and functions. Much of this has been covered in other reviews and will therefore be mentioned only in brief here. The most striking defect is abnormal nuclear morphology, including membrane lobulations and folds and irregular lamin staining. The membrane deformation increases in severity over time, correlating with increasing expression of both progerin and wild-type pre-lamin A [16]. The nuclear lamina of HGPS cells is also significantly thickened [16] and displays altered mechanical properties indicative of greater nuclear rigidity [17,18]. It is thought that the permanent farnesylation of progerin results in a more stable association with the nuclear membrane and reduced lamin dynamics [17,19]. This in turn may alter the arrangement of the lamin network [20], leading to the observed alterations in membrane deformation.

Significant alterations in internal nuclear architecture have been reported in progerin-expressing HGPS cells. Initial electron microscopic observations by Goldman et al. [16] identified disorganization of the peripheral heterochromatin. Subsequent studies have revealed reduced expression of heterochromatin-associated proteins and aberrant histone modification, suggesting that there are gross changes in chromatin organization [19,21]. Such defects would be predicted to cause changes in gene expression patterns, and one genome-wide expression study has reported widespread misregulation of genes, particularly those encoding extracellular matrix proteins [22]. Abnormal clustering of nuclear pores has been observed [16], and a recent report noted impaired nuclear import in HGPS cells [23].

In parallel with other premature aging disorders that target components of the DNA-maintenance machinery [24], genomic instability, persistent activation of DNA-damage checkpoints and defective DNA repair are features of HGPS [25,26]. The cause of the genomic instability is not clear, but may in part be due to increased sensitivity of HGPS cells to DNA damage [25]. Aberrant association of progerin with membranes during mitosis has also been observed, leading to mitotic defects and chromosome mis-segregation [27,28]. Together with increased telomere shortening [29,30], these defects are likely to contribute to the reduced proliferation and premature cellular senescence displayed by HGPS cells, which is the major feature of the HGPS phenotype.

Interestingly, cells from aged healthy individuals also exhibit altered nuclear architecture and express detectable levels of progerin, leading to the suggestion that progerin is linked to the normal aging process [27,31].

Is aberrant lamin A farnesylation the major determinant of HGPS?

Amid the plethora of biological abnormalities reported in HGPS cells, very little is known regarding which is the primary defect and which are subsequent downstream responses. Nuclear architecture defects are observed upon transient transfection of progerin constructs into wild-type cells and, indeed, nuclear envelope deformation is apparent within 1 h of introducing progerin into cells, indicating that the protein has an immediate and drastic dominant-negative effect on nuclear organization [16,19]. However, in HGPS fibroblasts, changes in histone methylation occur before nuclear envelope deformation becomes apparent [21], suggesting that membrane disruption is not the primary event.

It has generally been assumed that it is the aberrant farnesylation of lamin A that is the trigger for all the deleterious effects of progerin, but accumulating evidence suggests that this may not be the case. Some clues come from studies on cells treated with FTIs (farnesyltransferase inhibitors) which block the farnesylation of lamin A. Several groups have shown that FTI treatment reverses nuclear envelope deformation in progerin-expressing cells as well as in cells from patients with ZMPSTE24 mutations [3234]. Furthermore, chromosome segregation defects are ameliorated by FTI treatment [27]. These findings indicate that permanent lamin A farnesylation is the primary cause of these abnormalities presumably by causing tight and sometimes inappropriate membrane association. In contrast, some defects are not improved by FTIs, including mechanosensitivity [18] and DNA-damage defects [26], and a farnesylation-incompetent progerin mutant has the same ability as farnesylated progerin to induce DNA damage. These data highlight the need to carefully examine all progerin-induced cellular phenotypes when determining the efficacy of potential treatments.

The use of mouse models of progeria has proved very informative in this area. Several progeria models have been generated, including two that closely mimic the human diseases by either targeted introduction of the 150 bp LMNA deletion or disruption of the ZMPSTE24 gene [35,36]. In both cases, FTIs were found to improve several of the disease characteristics, including body weight, fat deposition and bone density, and also increased life expectancy. However, FTIs did not completely reverse the phenotype, but rather delayed its onset, with mice eventually succumbing to the same severe disease. In the light of this it is perhaps not surprising that, in a recent study, mice expressing a non-farnesylated version of progerin were found to exhibit a similar albeit milder phenotype to those expressing farnesylated progerin [37].

Thus it seems that aberrant farnesylation of progerin may not be the major factor leading to development of HGPS. This leaves two possibilities: either the internal deletion of 50 amino acids or the failure to remove the extreme C-terminal residues of pre-lamin A is at the root of the problem. It is not clear why an internal deletion should cause such a dramatic and severe phenotype compared with other laminopathies, but this large deletion may fundamentally alter the properties of lamin A and the entire lamin network [20]. A more attractive hypothesis, however, is that it is the continued presence of the C-terminal residues of pre-lamin A that is particularly toxic to the cell. This would explain how progeroid syndromes also arise from overexpression of wild-type pre-lamin A due to ZMPSTE24 mutations. In support of this model, Lattanzi et al. [38] found that expression of a farnesylation-incompetent pre-lamin A mutant induces the same changes in chromatin organization and histone methylation as seen in progeria cells. It would be interesting to confirm these findings in mice expressing the equivalent non-farnesylated version of wild-type lamin A. Of note, FTI treatment leads to a significant increase in pre-lamin A levels (presumably a non-farnesylated form) in both human and mouse cells expressing progerin [32,34,36], suggesting that this form of treatment may not be as effective as was first hoped.

Clinical implications

Although HGPS is a very rare disorder, it has aroused considerable interest in the scientific community, in part because of the devastating effect that it has on the affected children and their families, but also because of the potential link to the normal aging process. As a result of the concerted effort to uncover the molecular basis of the disease, research findings have led several groups to begin trials of drugs to ameliorate or reverse the disease process in HGPS children. Two trials, in Europe and in the U.S.A., are using FTIs in an attempt to prevent farnesylation of lamin A [39]. Interestingly, FTI treatment also improves cellular phenotypes in cells with LMNA mutations that do not affect lamin A processing [15,32], suggesting that the drugs may be applicable to progeria patients with a wide range of LMNA and ZMPSTE24 lesions.

Whereas FTIs may improve some aspects of the disease and increase life expectancy, evidence from mouse models suggests that this may not be sufficient to completely halt or reverse the disease process. An alternative approach has been tested by Scaffidi and Misteli [19], who targeted the cryptic splice site that generates progerin using morpholino oligonucleotides, to prevent its usage. In HGPS fibroblasts, this treatment effectively eliminated progerin expression and reversed several of the cellular phenotypes, including nuclear morphology, histone modification and gene expression defects. It is also encouraging to see that epidermis-related progeria phenotypes were reversed when progerin expression was switched off in mice with inducible keratinocyte-specific progerin expression [40]. It remains to be seen, however, whether oligonucleotides can be effectively administered to patients.

Our understanding of progeria has advanced dramatically in the few years since identification of the associated gene mutations and recent studies, particularly using mouse models, give hope that treatments will become a reality in the not-too-distant future.

Nuclear Envelope Disease and Chromatin Organization 2009: Independent Meeting held at College of St Hild and St Bede, University of Durham, Durham, U.K., 22–23 April 2009. Organized and Edited by Chris Hutchison (Durham, U.K.).

Abbreviations

     
  • FTI

    farnesyltransferase inhibitor

  •  
  • HGPS

    Hutchinson–Gilford progeria syndrome

  •  
  • MAD

    mandibuloacral dysplasia

We thank N. Sylvius for helpful discussions.

Funding

Our research is funded by the British Heart Foundation and the Wellcome Trust.

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