Genetic Disorders. Hutchinson-Gilford Progeria Syndrome HGPS is a lethal congenital disorder, characterised by premature appearance of accelerated ageing in children.
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Accumulation of progerin is thought to underlie the pathophysiology of HGPS. Individuals with HGPS appear to show ageing-related phenotypes at a much faster rate than normal, consequently leaving young children with the appearance and health conditions of an aged individual.
The observed male to female ratio of incidence of HGPS is 1. HGPS affect diverse body systems including growth, skeleton, body fat, skin, hair, and cardiovascular system. However, patients show no defects in their mental and intellectual abilities [ 6 - 8 ].
Surprisingly, progerin has also been found in normal unaffected individuals and its level increases with age, suggesting a similar genetic mechanism in progeria as in normal physiological ageing. Thus, numerous animal models have been developed to better understand the mechanism s of HGPS and to develop cure for this devastating disease.
In this chapter, the main aspects of HGPS such as signs and symptoms, genetic basis, animal models, and treatments will be discussed. The median age at diagnosis of HGPS is 2. The diagnosis is generally straightforward as affected patients show classical symptoms and strongly resembles one another. The affected individuals display no signs of disease at birth, but within their first years of life they gradually develop an appearance often referred to as aged-like [ 9 , 10 ].
Some of the typical physical characteristics of HGPS include alopecia loss of hair including scalp and eyebrows , prominent scalp veins and forehead, classical facial features including frontal bossing, protruding ears with absent lobes, a glyphic broad, mildly concave nasal ridge nose, prominent eyes, thin lips and micrognathia small jaw with a vertical midline groove in the chin [ 7 , 11 , 12 ] Figure 1.
Abnormal and delayed dentition is also common, and thin and often tight skin results from significant loss of subcutaneous fat [ 7 , 10 ] Figure 1. HGPS patients have high-pitched voices, a horse-riding stance, limited joint mobility and have short stature median final height of cm; median final weight of kg.
As they mature, they develop osteolysis, particularly involving the distal phalanges and clavicles [ 6 - 8 , 11 , 13 ].
Brothers with the Same Rare Condition (Growing up with Progeria)
This patient has typical phenotypes, including alopecia, thin and tight skin, loss of subcutaneous fat, prominent scalp veins and forehead, prominent eyes, protruding ears, thin lips, and small jaw. Photos were from courtesy of The Progeria Research Foundation. Recently, Olive et al. HGPS patients exhibited features that are classically associated with the atherosclerosis of ageing, including presence of plaques in the coronary arteries, arterial lesions showing calcification, inflammation, and evidence of plaque erosion or rupture.
Authors speculated that progerin accumulation in vascular cells causes nuclear defects and increases susceptibility to mechanical strain that in turn triggers cell death and inflammatory response, giving rise to atherosclerosis [ 14 ]. Interestingly, despite the presence of multiple premature ageing symptoms, many other organs, such as liver, kidney, lung, brain, gastrointestinal tract, and bone marrow, appear to be unaffected.
Furthermore, not all of the ageing processes are advanced in affected children.
For example, the prevalence of mental deterioration, cancer, and cataract, is not higher in HGPS patients [ 7 ]. To date, there are scarce explanations as to why only certain organs are affected in HGPS. Nevertheless, researchers have been trying to clarify some of these puzzling observations. Recently, Jung and colleagues suggested that the absence of cognitive deficits in HGPS patients may be explained by the down regulation of pre-lamin A expression in the brain [ 15 ].
In support of the result from this study, Nissan et al. Further studies, possibly using animal models, are required to investigate changes in the expression of miRNA-9 and its effects on the level of progerin in the brain.
The clinical features seen in HGPS strongly resemble several aspects of natural ageing.
Progeria chicken boy the book
For this reason, HGPS has served as a useful model for deciphering some of the mechanisms underlying physiological ageing. The first evidence for changes of nuclear architecture during the normal ageing process came from work in C.
In this study, the authors demonstrated that nuclear defects accumulate during ageing and suggested that HGPS may be a result of increased rate of the normal ageing process [ 17 ]. Scaffidi and Misteli showed that cells from HGPS patients and normally aged individuals share several common nuclear defects [ 18 ]. In addition, a small amount of progerin protein was detected in protein extracts derived from elderly individuals which was absent in young samples [ 19 ].
Rodriguez et al. Recently, Olive and others have also reported that although the level of progerin is much higher in HGPS patients, progerin is also present in the coronary arteries of non-HGPS ageing individuals and significantly increases with advancing age [ 14 ]. On the whole, accumulation of progerin, which is formed sparsely over time as a result of the ageing process, appears to be a possible candidate and partially responsible for cellular senescence and genomic instability that is observed in ageing cells.
In HGPS, this occurs at a substantially faster rate compared to normally-aged cells due to enhanced use of the cryptic splice donor site, producing higher level of progerin. The relationship between this disease of accelerating ageing and the onset of analogous symptoms during the lifespan of a normal individual is unclear.
Nevertheless, the idea that progerin may play a role in general human ageing is supported by the numerous studies mentioned above. The LMNA gene is known to be a hotspot for disease-causing mutations and has gained much attention due to its association with a variety of human diseases. To date, more than mutations spreading across the protein-coding region of the LMNA gene have been discovered see review [ 21 ].
The LMNA gene is found at chromosome 1q The B-type lamins are found in all cells and are expressed during development. Lamin A, C, B1 and B2 are key structural components of the nuclear lamina, an intermediate filament structure that lies on the inner surface of the inner nuclear membrane and is responsible for maintaining structural stability and organising chromatin see review [ 24 ].
The nuclear lamina determines the shape and size of the cell nucleus, and is involved in DNA replication and transcription. In addition, nuclear lamina has been shown to interact with several nuclear membrane-associated proteins, transcription factors, as well as heterochromatin itself.
There are more than 10 different disorders that are caused by mutations in the LMNA gene and these disorders are collectively called laminopathies and include neuropathies, muscular dystrophies, cardiomyopathies, lipodystrophies, in addition to progeroid syndromes see Chapter on Laminopathies.
The genetic basis for HGPS was unknown until it was found to be a single nucleotide mutation on the paternal allele with autosomal-dominant expression [ 3 , 4 ]. This mutation is located in exon 11 of LMNA gene and results in increased activation of the cryptic splice donor site, splicing the LMNA gene at 5 nucleotides upstream of the mutation, leading to accumulation of aberrant mRNA transcript, missing nucleotides from normal pre-lamin A.
It has been suggested that different mutations cause activation of the same cryptic splice site in exon 11 of LMNA gene, and disease severity is correlated with the usage of this splice site Figure 2. For instance, Moulson and others described two patients with particularly severe progeroid symptoms, clearly more severe than a typical case of HGPS [ 30 ].
In both cases, the amount of progerin relative to properly processed pre-lamin A was significantly greater than that of in typical HGPS, suggesting that the severity of the disease appears to be dependent on the amount of progerin in cells [ 30 ].
Very recently, another more severe case was reported by Reunert et al [ 31 ]. This patient had the heterozygous LMNA mutation c. Authors showed that the ratio of progerin protein to mature lamin A was higher in this patient compared to classical HGPS and also proposed that this ratio determines the disease severity in progeria [ 31 ]. Opposite cases were also shown by Hisama and colleagues. In this study, mutations at the junction of exon 11 and intron 11 of the LMNA gene resulted in a considerably lower level of progerin compared to HGPS, giving rise to an adult-onset progeroid syndrome closely resembling Werner syndrome [ 33 ].
A schematic diagram showing point mutations leading to increased activation of a cryptic splice site within exon 11 of the LMNA gene [4, 30, 31, 33]. It is interesting to note that the normal LMNA sequence can also be spliced abnormally, removing nucleotides of exon 11, in healthy individuals and this incidence may increase with age, leading to cellular senescence [18, 20].
Under the normal condition, mature lamin A protein is produced from a precursor, pre-lamin A, via a series of post-translational processing steps, which begins at the C-terminal end. The CaaX motif at the C-terminal tail where the C is a cysteine, the a residues are aliphatic amino acids, and the X can be any amino acids signals for 4 sequential modifications Figure 3A.
Following this cleavage, farnesylated C-terminal cysteine is methylated by isoprenylcysteine carboxy-methyl transferase ICMT. Consequently, a truncated lamin A protein that is, progerin remains farnesylated, which is believed to have a dominant negative effect in HGPS.
In HGPS, the first 3 steps of post-translational maturation can be performed that is, farnesylation, cleavage, and methylation , while the fourth processing step cannot be completed as the GG mutation eliminates the second cleavage site recognised by ZMPSTE24 of pre-lamin A resulting a permanently farnesylated form of progerin Figure 3B [ 34 ].
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This improperly processed protein in HGPS is thought to underlie the progression of the disease phenotype [ 35 ]. Because progerin, unlike mature lamin A, remains farnesylated, it gains a high affinity for the nuclear membrane, consequently causing a disruption in the integrity of the nuclear lamina. Indeed, HGPS patient cells show a number of abnormalities in nuclear structure and function.
These features worsen with passages in cell culture and are correlated with an apparent intranuclear accumulation of progerin Figure 4 [ 36 , 38 ]. In addition to permanent farnesylation of the progerin, it has been hypothesised that the deletion of the phosphorylation site Ser found in the 50 amino acid-deleted region may also account for some of the HGPS phenotypes as cell cycle dependent phosphorylation of lamin A is important for its normal function [ 4 , 39 ].
Immunostaining of skin fibroblasts taken from a normal individual left and a HGPS patient right showing nuclear blebbing.
Note that the expression of lamin B1 is lost in the blebbed region. The figure has been adapted from Shimi et al. Numerous studies have addressed the senescent characteristics of HGPS cells, which intriguingly parallel with properties of fibroblasts from aged individuals. Cellular senescence is a hallmark characteristic of the ageing process, and cell nuclei from old individuals have similar defects to those of HGPS patient cells, including increased DNA damage [ 18 , 41 , 42 ], down-regulation of several nuclear proteins, such as the heterochromatin protein HP1 and the LAP2 group of lamin A-associated proteins [ 18 , 37 ], and changes in histone modifications [ 18 ].
Heterochromatin becomes more disorganised with increased ageing in patients [ 43 ], and deregulation of chromatin organisation is a common phenomenon in HGPS, where progerin is known to alter histone methylation [ 44 , 45 ].
To directly demonstrate that the production of progerin by sporadic use of the cryptic splice donor site in LMNA exon 11 is responsible for the observed changes in nuclear architecture in cells from aged individuals, Scaffidi and Mistelli used a morpholino oligonucleotide to inhibit this cryptic splice site and consequently the production of progerin and showed that the nuclear defects were reversed [ 18 ].
Although the amount of progerin in cells is considerably lower than the amount of lamin A and lamin C [ 46 ], it is obvious that this small amount of progerin is very potent in terms of causing disease phenotypes in humans and in causing misshaped nuclei in cultured cells.
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Supporting the hypothesis that progerin exerts dominant negative effect in HGPS, Goldman and colleagues introduced progerin into normal cells via transfection and showed that progerin is targeted to the nuclear envelope and is entirely responsible for the misshapen nuclei. Same changes were observed when progerin protein was microinjected into cytoplasm of the normal cells [ 36 ].
It was hypothesised that retention of the farnesyl group on progerin may be the key factor in the development of the HGPS phenotype. Indeed, several different research groups showed that the nuclear abnormalities were alleviated or reversed by the inhibition of farnesylation [ 47 - 49 ]. These overlapping and distinct clinical features of atypical HGPS are well described by Garg and colleagues [ 51 ].
Animal models of HGPS have been a valuable tool in the study of the pathological processes implicated in the origin of this disease as well as finding a cure. Some of these mouse models are designed to express the exact mutation that is observed in human HGPS patients, or have defect in the lamin A processing.
Hutchinson-Gilford Progeria Syndrome
These mouse models are summarised in Table 1. Although this animal model did not display any external phenotypes seen in HGPS patients, such as growth retardation, alopecia, micrognathia and abnormal dentition, it progressively lost vascular smooth muscle cells in the medial layer of large arteries that closely resembled the most deadly aspect of the HGPS patients. Surprisingly, these animals showed no differences in their life expectancy compared to their wild-type littermates [ 52 ].
Disruption of the gene encoding ZMPSTE24 in mice causes defective lamin A processing, which results in the accumulation of farnesylated pre-lamin A at the nuclear envelope [ 54 , 55 ]. Since these ZMPSTE24 -deficient mice have shown to have many features that resemble HGPS and other laminopathies diseases that are caused by mutations in the nuclear lamina , this model has served as a crucial tool to explore the mechanisms underlying these diseases and to design therapies for the treatment [ 55 , 56 ].
Furthermore, loss of ZMPSTE24 in humans has been shown to cause restrictive dermopathy, a lethal perinatal progeroid syndrome characterised by tight and rigid skin with erosions, loss of fat and prominent superficial vasculature, thin hair, micrognathia, joint contractures, and thin dysplastic clavicles [ 58 ].
Furthermore, they show progressive hair loss, abnormal teething, muscle weakness, which ultimately lead to premature death at the age of weeks [ 54 , 55 ]. The results from this study not only suggest that the accumulation of the farnesylated pre-lamin A is toxic, but also show that lowering the level of pre-lamin A have a beneficial effect on disease phenotypes in mice and on nuclear shape in cultured cells [ 59 ].
These animals show several HGPS-related phenotypes, including bone alterations, reduction in subcutaneous fat and premature death at around 28 weeks of age [ 47 , 60 ].
These animals exhibit severe growth retardation with complete absence of adipose tissue and numerous spontaneous bone fractures.
They die at weeks of age with poorly mineralised bones, micrognathia, craniofacial abnormalities [ 60 ].
In all of the mouse models described above, both pre-lamin A and progerin are farnesylated.