Hutchinson-Guilford Progeria Syndrome progeria or HGPS is a rare autosomal dominant disorder which results in premature aging and eventually death. Most tissues and various organs display premature degeneration, and so are referred to as "accelerated aging disorders". Currently, only 100 cases of progeria have been formally documented, 50 of which are alive today. The identification of the HGPS gene has only recently been identified and located on codon 608 of the LMNA gene, which codes for four types of lamins. This discovery has allowed us to identify the main cellular and moleculr mechanisms that bring about the progeroid phenotype and so perhaps will bring us closer to finding treatment and even a cure.
Normal Physiological aging
Aging on an evolutionary level may be described as a progressive decline in fitness (the ability to survive and reproduce) due to a decline in tissue functionality with increasing age (Partridge, 2001). On a cellular level it may be described as a progressive functional decline and increase in cell mortality (Lombard et al., 2005). Although many theories have been proposed, no conclusive theory has been agreed upon to explain how or why we age.
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Aging is thought to be caused by various genetic and environmental factors. At the cellular level this progressive malfunction of tissue is thought to be due to accumulation of damage by various biomolecules which lead to cell loss or damage. Usually the body has the ability to regenerate these damaged or lost cells through pools of stem cells, however the body does not have the ability to regenerate infinitely and over time this causes a decline in tissue functions typical of aging. This is consistent with the disposable soma theory of aging, which states that cell repair and maintenance (including DNA repair, defence against oxidants, etc) are costly activities. To work to extend life indefinitely would make little sense, as in the wild many organisms have an extremely high mortality rate. Therefore, animals have evolved in such a way that energy invested in maintaining the soma is limited, so that the animal is kept alive long enough for it to reproduce, but not to keep it alive indefinitely. Past this point, the body's regeneration mechanisms fail and physiological aging becomes apparent. From an evolutionary point of view, this theory makes more sense than others which are based around aging being a genetically inbuilt process, as this would provide no benefit whatsoever to the individual animal or the species as a whole.
Aging may involve damage to a variety of cellular components, however damage to various DNA and RNA is likely to be a major contributing factor. Despite the cell's inbuilt mechanisms designed to repair damage, impaired DNA which has not been restored perfectly can lead to mutations with detrimental organismal consequences. Balaban et al. (2005) outlines the potential role for damaged mitochondria DNA in the process of aging, however a more likely culprit is nuclear DNA. Mitochrondial DNA has thousands of copies present within the cell which can be replaced if damaged, whereas there are only two copies of nuclear DNA. Several studies have shown that as age increases, so does the risk of mutation. There is substantial evidence to suggest a causal link between damage to nuclear DNA and physiological aging. Sedelnikova et al. (2004) showed that the level of double strand breaks (DSBs) that occur increase with age and older cells are less able to repair these DSBs. Finally, there is the observation that symptoms of progeria are caused by mutations in DNA maintenance proteins, which leads to impaired DNA repair mechanisms.
HGPS belongs to a group of disorders known as segmental progeroid syndromes, characterised by early manifestation of features usually associated with normal physiological aging. They are consequently referred to as "accelerated aging disorders".
HGPS was first described over 120 years ago by Hutchinson (1886) and again later by Guilford (1904). Since its original classification in 1886, just over 100 cases of the disease have been documented. It affects around 1 in 4-8 million newborns all over the world with no preference for gender.
Figure - Locations of children around the world who have been diagnosed with HGPG : Adapted from the Progeria Research Foundation. There are currently 50 living children diagnosed with HGPS, most of which reside in affluent Western countries. It is estimated that a further 150 children worldwide suffer from progeria but have not yet been identified due to insufficient means to diagnose in less prosperous countries as well as the rarity and complexity of the disease and the fact that the HGPS gene has only recently been identified.
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Children with progeria are born appearing healthy, however at shortly after birth it becomes apparent that weight and height gain are below that of which is expected of healthy children (Merideth et al., 2008). By 18-24 months of age they begin to display signs of premature aging, which can be seen in figure 2 below.
Figure : A 3 and a half year old boy with HGPS showing typical progeroid symptoms. These include stunted growth, loss of hair and body fat, aged skin and unusual facial expression. Non-visible symptoms include stiff joints and atherosclerosis.
Impaired growth does not seem to be due to any hormone inbalance/resistance or malnutrition. Cardiovascular problems are generally thought to be caused by loss of smooth muscle cells, disruption of the extracellular matrix and other irregularities in vascular structure. Life span ranges from 8 - 21 years with the average being around 13 years old. Death is almost invariably caused by atherosclerosis.
HGPS has recently been acknowledged as part of a family of diseases known as laminopathies, as it is caused by a dominant mutation on the LMNA gene. Before the identification of the gene responsible for progeria, diagnosis was carried out solely on the symptoms that have been mentioned. Thanks to the recent discovery of the mutated gene (Eriksson et al., 2003), diagnosis can be carried out based on the appearance of this mutation. HGSP is caused by a de novo mutation on the LMNA gene, although other progeroid syndromes may be hereditary.
The LMNA gene codes for the nuclear A-type lamin proteins: lamin A, lamin C, lamin A10 and lamin C2. These, along with the B-type lamin are responsible for keeping the structure of the nucleus together by forming a scaffold which lines and interacts with the nuclear membrane. The structure of the nuclear lamina within the nuclear envelope is shown in figure 3.
Figure : Structure and function of the nuclear lamina - Coutinho et al. (2009). The lamina exists on the inner nuclear membrane (INM), providing structural support and helping with chromatin organisation as well as binding nuclear pore complexes (NPCs), nuclear proteins (purple) and transcription factors (pink). Barrier to auto integration factor (BAF) is a chromatin-associated protein which binds to the lamina and various nuclear envelope proteins.
Fawcett (1966) deduced that the nuclear lamins are components of the nuclear lamina, a layer found between the chromatin and the nuclear envelope initially thought to provide structural support for the nuclear membrane and provide an anchorage location for the chromatin. Recently, further roles of nuclear lamins have been proposed, including DNA synthesis, transcription, apoptosis and assembly of the nuclear envelope.
It has been determined that several isoforms of lamins have are coded for by three different genes: As previously mentioned, the LMNA gene codes for lamins A, Aâˆ†10, C and C2 (Fisher et al., 1986). The LMNB1 gene encodes lamin B1 and LMNb2 encodes B2 and B3 lamins (Stuurman et al., 1998). Whilst every vertebrate cell expressed at least one type of B lamin, lamins encoded by the LMNA gene are only expressed in differentiated tissue. In mouse development, the earliest detection of lamin A is after 9 days in the trophectoderm (Prather et al., 1991). In most embryonic tissues, lamin A is undetectable until much later stages in development and some LMNA products are only identifiable post natally. These observations suggest that lamin encoded by LMNA may have specific roles within certain cells. It has been suggested that the role of these lamins was in fact to induce or maintain the differentiated state, however this was refuted by a study carried out by Peter and Nigg (1991). It is likely, however, that A type lamins have roles related to and dependant on correct chromatin organisation and nuclear structure. This includes reformation of the nuclear envelope post-mitosis (Holaska et al., 2003), DNA replication (Moir et al., 2000), transcription (Spann., 2002) and nuclear positioning (Haque et al., 2006). Although studies have shown that LMNA deficient mice develop normally, shortly after birth growth problems and muscular dystrophy occur (Sullivan et al., 1999)
Shortly before cell division in the late prophase stage of the cell cycle, the nuclear envelope breaks down, involving the dismantling of the nuclear lamina. This is initiated by the phosphorylation of lamin subunits, forming lamin monomers, dimers and tetramers. A type lamins are the first to be disassembled, occurring during early prophase, whilst B type lamins are disassembled during prometaphase (Georgatos et al., 1997). This process is thought by some to be necessary for the reassembly of the nuclear envelope after cell division have taken place (Burke and Gerace, 1986) however studies such as Newport et al. (1990) have provided evidence against these theories, stating that when these disassembled lamin subunits are imported, they are done so into a formed nuclear envelope with fully functional pores. Perhaps is it possible that a finite number of lamin monomers are used in the reassembly of the nuclear envelope and the rest are transported in at a later stage.
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The role of lamins in DNA replication is unclear, however several studies have suggested that tXenopus interphase extracts were immunodepleted of Lamin B3 which resulted in a lack of DNA replication (Newport et al., 1990; Meier et al., 1991), however it remained unclear whether this was entirely due to the absence of lamins or if other factors, such as a smaller and more fragile nuclear envelope, contributed. A later study by Moir et al. (2000) provided evidence to suggest that normal nuclear lamin organisation is required for DNA synthesis and that this dependency is completely unrelated to the formation of the nuclear envelope. It appears that when nuclear lamin organisation is incorrect, the elongation phase of replication fails to transpire, probably due to an alteration in distribution of elongation factors, Replication Factor Complex (RFC) and Proliferating Cell Nuclear Antigen (PCNA).
The potential role of nuclear lamins in transcription has been put forward by Spann et al. (2002), who disrupted the normal nuclear organisation of nuclear lamins using a dominant negative mutant lamin lacking the NH2- domain. This resulted in the inhibition of polymerase II activity in both mammalian and embryonic Xenopus cells. Notably, polymerases I and III were not affected.
The role of lamins in apoptosis is directly related to the state of the nuclear envelope. Apoptosis is a very precise physiological mechanism for effective destruction of unwanted cells without causing inflammation or distress to other cells, as would occur in necrosis. Lamin degradation is one of the processes that occur during apoptosis, however several studies have suggested nuclear lamins play a role in the induction of apoptosis. As previously mentioned, B type lamins are essential for cell survival. Post mitosis, PP1 is targeted to the nuclear envelope to initiate lamin B reformation. If this process is abolished, lamin B is degraded in a caspase formation and apoptotic signals take place. As previously mentioned, expression of lamins A/C is limited to differentiated cells. Due to their role in DNA replication and transcription, several researchers have hypothesised that they play a role in gene expression as well. Gupta and Saumyaa (2008) propose that specialised L/A lamin expression regulate gene expression in such a way which may prevent cell division and cause the cell to undergo terminal differentiation - a form of programmed cell death.
Lamins are also undoubtedly used for chromatin organisation and positioning within the nucleus, as multiple studies have suggested. Cells with LMNA mutations exhibit a range of problems involving abnormal chromosome organisation. Glass et al (1993) showed that A lamins interact with chromatin by binding histones as well as indirectly through lamin-binding proteins such as LAP2Î± and barrier-ro-autointegration (BAF) (Holaska et al., 2003).
The most commonly reported mutation responsible for causing HGPS is LMNAÂ codon 608 in exon 11 (c. 1824 C>T). Although the LMNA gene encodes both A and C type lamins, only A lamins are affected as exon 11 is not present in lamin Cs. Although this point substitution does not result in an amino acid change (G608G ) it partially activates cryptic splice site resulting in the deletion of ~50 amino acids near the carboxyl terminal in lamin A (LAâˆ†50) but maintaining the CAAX site. Amongst the deleted amino acids is the ZMPSTE24 cleavage site, which is necessary for the maturation of lamin A. This results in farnesylation and carboxymethylation of lamin A, resulting in "progerin". This cryptic splice site is only partially activated and it is estimated that only 10-50% of splices mRNA in transcribed. Since the second LMNA allele is normal, there is still some presence of wild-type lamin A although it is present in much lower levels. Whilst most HGPA probands are heterozygous for LMNA p.G608G, mutations have been reported on other location on the LMNA gene, such as one patient with a p. E145K mutation and another with 471C and R527C mutations (Goldman et al., 2002). This mutations have lead to various laminopathies very similar to HGPS (often referred to as atypical HGPS) however the pathophysiological manifestation of these diseases is probably different as they do not result in the production of progerin.
Cellular and molecular causes of HGPS
HGPS cells are significantly larger than normal cells and usually have large cytoplasmic vacuoles, an abnormally shaped and sized nucleus, often distorted with chromatin extrusion (De Sandreâ€Giovannoli et al., 2003). Goldman et al. (2004) also report evidence of misshapen nuclear envelopes and abnormally thick lamina, both of which are associated with other mutations on the LMNA gene. Not surprisingly, these structural abnormalities cause a variety of cellular dysfunctions including loss of structural nuclear integrity and more importantly, certain mitotic problems. These include abnormal chromosome segregation, delays in cytokinesis and nuclear assembly andbinucleation (Dechat et al., 2007) HGPS cells have abnormal chromosome organization in interphase nuclei and can show a loss of peripheral heterochromatin, possibly due to various epigenetic changes. These include upregulation of genes such as H3K9me3 and H4K20me3, both of which are involved in the definition of constitutive heterochromatin (Columbaro, 2006). The H3K27me3, responsible for the definition of facultative chromatin, is downregulated, possible due to a reduction in the expression of the histone methyltransferase enhancer EZH2 used for H3K27 trimethylation (Schumaker et al., 2006). Evidence has suggested that these changes in heterochromatin due to gene expression may often result in further changes in gene expression (Schumaker 2006).
Allsopp et al. (1992) reported that primary cells obtained from HGPS patients have significantly shorter telomeres than aged-matched controls. This study, however, was carried out before the identification of the HGPS gene mutation, so diagnosis was carried out on symptoms alone. This means that the type of progeroid syndrome these patents had may have varied from the 608 mutation.
Several studies have indicated that HGPS cells show increased damage to DNA. This was demonstrated by Bridger and Kill (2004) whose experiments showed that HGPS cells were unable to proliferate sufficiently when kept in culture and showed increased rated of apoptosis. These cells also demonstrated early signs of cellular aging. All of these afflictions are caused by damage to nuclear DNA. Lui et al (2006) also demonstrated that HGPS cells have increased activity in their DNA repair pathways, strongly implying that DNA damage has occurred. The most compelling evidence to suggest DNA damage as a likely culprit for progeroid symptoms is presented in a previous study by Lui et al. (2005), which showed that HGPS cells have a double strand break (DSB) repair defect. These cells show less concentrated levels of DSP repair factors such as Rad50 and Rad51 as well as damage signaling molecules such as 53BP1. With this evidence, the conclusion can be drawn that Lamin A in necessary for complete DNA repair to take place when necessary, and also that DSB repair is diminished in HGPS cells.
Many of the changes to the nuclear membrane are not a direct result of insufficient lamin A, but instead are caused by the presence of Progerin, an abridged version of lamin A, and it's accumulation of the INM. This accumulation results in alterations in the structure of the nuclear lamina. Lui et al. (2005) suggests that the inefficient DNA repair mechanisms which occur in HGPS cells are in fact due to raised levels of Progerin at the INM. Fitting with this theory, studies aimed at reducing the levels of Progerin have successfully managed improve the cellular phenotype of HGPS cells. Scaffidi and Mistelli (2005) proposed inhibiting the production of Progerin whilst leaving lamin A unaffected by using specific antisense morpholinos which inhibit splicing at the deviant site. Another approach is to treat HGPS cells with farnesly transferase inhibitors (FTIs) which, as the name suggests, inhibit farnesyl transferase, so preventing the modification of Progerin to the farseylated kind seen in HGPS cells. Lui et al., (2006) has shown that this approach does not only improve the cellular and nuclear abnormalities of HGPS cells, but can actually improve the health of HGPS mice. However, FTIs are not specific to Progerin as antisense morpolinos are, and lamin A is likely to be inhibited as well as the modification of Progerin. It is also possible that several other unrelated proteins would be affected by this approach, however these negative side-effects have not yet been documented.