DEFINITION
Hutchinson–Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder caused by mutations in the LMNA gene, which is characterized by premature, rapid aging shortly after birth.
In 1886, the general practitioner Jonathan Hutchinson described a 3 ½-year-old boy with ‘congenital absence of hair and mammary glands with atrophic condition of the skin and its appendages’ [Hutchinson, 1886]. He thought it was a form of ectodermal dysplasia. A second patient was mentioned briefly by Hutchinson in 1895 but described in much more detail by Hastings Gilford [1897] who had followed the patient for several years until his death at 17 years. Gilford provided follow-up data on the original patient described by Hutchinson, and recognized that at least some of the symptoms resembled early aging. In a subsequent publication, he suggested naming the entity ‘progeria,’ ‘pro’ meaning early and ‘geras’ meaning old age in ancient Greek [Gilford, 1904].
EPIDEMIOLOGY
The reported incidence of HGPS is 1 in 8 million, though the true figure might be closer to 1 in 4million, taking into consideration unreported or misdiagnosed cases. Since 1886, just over 100 cases of HGPS have been reported and currently there are approximately 40 known cases worldwide.
A literature search of 132 patients gave a ratio of 69 males to 57 females (1.2:1). In the 23 living European patients, the sex ratio is equal (11:12).
Hutchinson-Gilford progeria syndrome 2004
Hutchinson-Gilford progeria syndrome: review of the phenotype 2006
PATHOGENESIS
Interest in progeria increased further when both a French and an American group discovered that the disorder was caused by mutations in the gene encoding Lamin A/C. Lamins are a family of nuclear proteins that belong to the intermediate filaments and are key structural proteins of the nuclear lamina. They oligomerize to form a filamentous lattice that provides structural support for the nucleus.
The eukaryotic nucleus contains the chromosomes and is a complex organelle where major cellular processes, such as DNA replication, RNA transcription and processing, and ribosome assembly take place. The function of the nucleus highly depends on its structural organization and the dynamic structural rearrangements occurring in cell differentiation and cell cycle progression. The nuclear envelope (NE) enwraps the DNA and forms the border between the nucleus and cytoplasm. It is composed of inner and outer nuclear membranes that are separated by the perinuclear space and contain nuclear pore complexes mediating nucleo-cytoplasmic transport. The outer nuclear membrane is continuous with the endoplasmic reticulum and is also directly linked to the inner membrane at sites of nuclear pore complexes. Underneath the inner membrane is a meshwork of nuclear-specific intermediate filaments, termed the nuclear lamina, which includes lamins plus a growing number of lamin-associated proteins, which regulate lamin assembly and function. Biochemically, the nuclear lamina is defined as the peripheral nuclear structure that remains insoluble after extraction of nuclei with non-ionic detergents, salt and nucleases. However, the lamina is only a subfraction of the detergent-salt-resistant structural framework, which runs throughout the nuclear interior and organizes nuclear space and is often referred to as nucleoskeleton or nuclear matrix. The nuclear scaffold is supposed to provide mechanical stability for nuclear structure, to form a platform for most metabolic nuclear processes, and to organize chromatin in a three-dimensional nuclear space and thus regulate gene expression at the chromatin structure level.
The core structure of the nuclear lamina is formed by type V intermediate filament proteins, the lamins. They assemble to a meshwork of tetragonally organized 10-nm filaments underneath the inner nuclear membrane. Vertebrates have three lamin genes (LMNA, LMNB1, LMNB2) encoding at least seven distinct isoforms. B-type lamins (lamins B1 and B2) are encoded by distinct transcripts originating from the LMNB1 and LMNB2 genes and are constitutively expressed throughout development in every cell. A-type lamins, comprising lamin A and its smaller splice variant lamin C, are generated by alternative splicing of the RNA transcribed from the LMNA gene and are only expressed in later stages of development and in differentiated cells in a tissue-specific manner. The first 566 amino acids of lamins A and C are identical, but their carboxyl-terminal domains diverge. Lamin A but not lamin C is synthesized with a conserved CaaX (cysteine–aliphatic amino acid–aliphatic amino acid–any amino acid) motif in its carboxyl terminal ends that is subjected to sequential processing steps to generate the mature forms of lamin A, lamin B1 and lamin B2. First a farnesyltransferase adds a 15-carbon farnesyl isoprenoid to the carboxyl terminal cysteine (CaaX). Farnesylated lamins are then modified by one of two prenyl-CaaX-specific endoproteases, named RCE1 and ZMPSTE24, that removes the tripeptide at the carboxyl terminus of prelamin A. The carboxyl terminal farnesylcysteine is then methylated by an isoprenylcysteine carboxyl methyltransferase (ICMT). Prelamin A undergoes an additional step mediated by ZMPSTE24, which cleaves the carboxyl terminal 15 amino acids releasing the mature, unfarnesylated and unmethylated lamin A, which contains 646 amino acids. The precise role of these processing events is not well understood. As farnesylation and carboxymethylation increase the hydrophobicity of a protein, it is likely that these modifications facilitate the accurate targeting of the final lamin A product to the nuclear envelope. The fate of the carboxyl terminal peptide released by ZMPSTE24 cleavage is unclear, and it could remain anchored to the membrane or be rapidly degraded.
At least 20 distinct mutations in the LMNA gene have been linked to HGPS, however the most frequent is a point mutation at position 1824 that activates a cryptic splice site donor. This leads to the production of a mutant prelamin A protein with an internal 50 amino acid deletion lacking the terminal ZMPSTE24 cleavage site but not affecting the C-terminal CaaX motif. As a consequence, the mutant HGPS prelamin A, which has been termed progerin, remains permanently farnesylated and carboxymethylated. The production of progerin leads to the progressive appearance of a number of cellular alterations including severe growth defects and altered nuclear membrane morphology that collectively manifest as an early onset of an aging phenotype. The affected children generally succumb to cardiovascular problems and similarities between many aspects of cardiovascular disease in progeria patient and normal adult individuals with atherosclerosis have recently been reported. Ectopic expression of progerin in normal diploid fibroblasts recapitulates most if not all the phenotypes of progeria cells suggesting that the mutant protein acts in a dominant negative manner. It is not surprising that mutations in the ZMPSTE24 gene, whose product is required for the last cleavage step in the prelamin A processing pathway that affect the activity or synthesis of this protein, cause MAD and RD, respectively, two progeria-like human diseases characterized by growth retardation, skeletal abnormalities and cutaneous atrophy. Studies have suggested that aberrant splicing of the prelamin A RNA leading to the production of progerin may play a role in general human aging. Furthermore, alterations in the normal prelamin A processing pathway have also been implicated in aging of the vascular system in the absence of progerin, as demonstrated by a recent study showing that prelamin A accumulates in vascular smooth muscle cells (VSMCs) of aged individuals but not of young individuals. Here, the accumulation of prelamin A is the result of a decrease in the levels of ZMPSTE24, suggesting an age-dependent decline in the activity of this critical processing enzyme.
The molecular basis of the toxicity induced by partially processed forms of prelamin A is poorly understood. First, accumulation of progerin or farnesylated prelamin A may cause abnormalities in the structure of the nuclear membrane and render the cell more susceptible to damage caused by physical stress. While this model may explain some of the phenotypes observed in progeria cells, it is evident that lamin A, by controlling nuclear structure, is also influencing fundamental nuclear processes either indirectly, or by making direct contacts with chromatin and transcription factors. It is documented that accumulation of progerin alters the functional organization of chromosomes by causing changes in the distribution and levels of heterochromatin as well as abnormal telomeres length homeostasis. These epigenetic changes are likely to influence gene expression, as evident from the large number of genes that are expressed differentially in HGPS cells as compared to normal cells. Remarkably, heterochromatin organization can be recovered by combined treatment with inhibitors of farneysltransferase and histone deacetylases, suggesting that these changes can be reversed by pharmacological treatment. Progerin has not been reported to interact with or directly influence histone acetyltransferases or deacetylases, yet altered levels or localization of other regulators of chromatin structure have been observed in progeria cells. These findings suggest that changes in these and possibly other chromatin remodeling and modifying factors contribute to the alteration in the epigenetic organization of chromatin induced by progerin.
Lamin A has been shown to bind several transcription regulators, including the retinoblastoma protein (Rb) and c-Fos, and these interactions influence the localization and function of these factors. Whether accumulation of progerin influence the localization of this set of transcription factors and changes in their activity contribute to the onset of progeria has not been investigated extensively. However data from genome wide expression profiling studies indicate that progerin expression is accompanied by alteration in the expression of genes whose expression is regulated by Rb, and these changes are reversed upon FTI treatment. Collectively these studies underscore the concept that accumulation of progerin influences the levels and spatial localization of transcriptional regulators, which, in combination with changes in the epigenetic make up of the chromatin, is likely to contribute to the altered landscape of gene expression observed in progeroid cells.
Progeria cells undergo a short period of hyperproliferation followed by apoptosis and senescence and activation of p53 is a key feature of progeria cells, cells with defective prelamin A processing pathway (Zmpste24 knockout mice) and cells expressing ectopic progerin. However, the precise mechanism of p53 activation and whether this activation is linked to both premature senescence and apoptosis in progerin-expressing cells remains to be established. DNA damage may be an inducer of p53 since progeria cells as well as cells from progeria mice models display phosphorylated histone 2AX (γH2AX) foci, a marker of DNA breaks . In cultured fibroblasts, p53-dependent senescence or apoptosis could be triggered in response to DNA damage triggered by either telomere attrition or dysfunctional DNA repair, as both processes activate a DNA damage-signaling pathway. Published data suggest that both processes may contribute to growth dysfunction induced by progerin.
Dynamic Connections of Nuclear Envelope Proteins to Chromatin and the Nuclear Matrix
Lamin A, farnesylation and aging 2012
Investigating the purpose of prelamin A processing 2011
Cardiovascular pathology in Hutchinson-Gilford progeria: correlation with the vascular pathology of aging 2010
Prelamin A acts to accelerate smooth muscle cell senescence and is a novel biomarker of human vascular aging 2010
SYMPTOMS
Children born with HGPS typically appear normal at birth, but within a year they begin to display the effects of accelerated aging.
Typical facial features include micrognathia (small jaw), craniofacial disproportion, alopecia (loss of hair), and prominent eyes and scalp veins.
Children experience delayed growth and are short in stature and below average weight. Due to a lack of subcutaneous fat, skin appears wrinkled and aged looking. Other key abnormalities include delayed dentition, a thin and high pitched voice, a pyriform (pear-shaped) thorax, and a ‘horse riding’ stance.
As they mature, the disorder causes children to age about a decade for every year of their life. This means that by the age of 10, an affected child would have the same respiratory, cardiovascular, and arthritic conditions as a senior citizen. On average, death occurs at the age of 13, with at least 90% of HGPS subjects dying from progressive atherosclerosis of the coronary and cerebrovascular arteries.
Hutchinson-Gilford progeria syndrome: review of the phenotype 2006
DIAGNOSIS
The diagnosis of HGPS is usually straightforward, and the classically affected patients strongly resemble one another. However, there is a group of patients with progeria that show a definite overlap with patients with mandibulo-acral dysostosis (MAD). Their clinical findings differ from classical HGPS in several respects:
a. Growth is less retarded, adult heights varying from 130 to 145 cm, while in classical HGPS height rarely exceeds 115cm;
b. In many, scalp hair persists much longer, and may not disappear completely even in old age;
c. The lipodystrophy progresses more slowly with fat pads remaining in the cheeks, submandibular region, and pubis into adulthood;
d. Osteolysis is more severe in all affected bones (vault, mandible, clavicles, ribs, distal phalanges) except for the viscerocranium where it is mild in childhood and only gradually progresses later on. The more severe osteolysis increases the risk of fractures, especially of the humerus, often at a young age (in 10 of the families, affected children had fractures, usually from the age of 2–3 years);
e. The incidence of consanguinity is increased (4/14 families);
f. The chance of survival into adulthood is some what increased (four cases having reached an age of 20 years or above).
In classical HGPS, the main reason for presentation was failure to thrive (55%), hair loss (40%), skin problems (28%), lipodystrophy (20%), and rarely other symptoms (unusual face; small clavicles; affected sib) (the total is more than 100% as several patients presented with more than one symptom).
The mean age at diagnosis in literature cases was 2.9 years (data available on 72 patients). In the European patients, it was 2.6 years (1.1–4.8 years).
Clinical Tests
- On X-rays or at sonography, the heart appears enlarged.
- ECG shows signs of impaired coronary functioning and enlargement of the left ventricle, either at rest or on treadmill exercise testing
Hutchinson-Gilford progeria syndrome: review of the phenotype 2006
Genetic Test
A genetic test for Hutchinson-Gilford progeria syndrome is currently available. In the past, doctors had to base a diagnosis of progeria solely on physical symptoms, such as skin changes and a failure to gain weight, that were not fully apparent until a child's first or second year of life. This genetic test now enables doctors to diagnose a child at a younger age and initiate treatment early in the disease process.
http://www.genome.gov/
http://www.progeriaresearch.org/
INHERITANCE
Classical HGPS is an autosomal dominant disorder, each patient arising through a spontaneous mutation in LMNA, consistent with the increased mean parental age.
Parents and siblings of children with progeria are virtually never affected by the disease. In accordance with this clinical observation, the genetic mutation appears in nearly all instances to occur in the sperm prior to conception.
Non-classical progeria has been reported as an autosomal recessively inherited disorder, either because of parental consanguinity or because of recurrence in siblings.
LMNA mutations acting as an autosomal recessive trait without any heterozygote phenotype have been reported.
Hutchinson-Gilford progeria syndrome: review of the phenotype 2006
ALLELIC HETEROGENEITY
A plethora of mutations has been identified within Lmna, making HGPS and atypical progerias just one of at least nine genetic disorders associated with this gene:
- Striated muscle diseases
- Autosomal and recessive forms of Emery–Dreifuss muscular dystrophy (AD/AREDMD)
- Dilated cardiomyopathy type 1A (CMD1A)
- Limb–girdle muscular dystrophy type 1B (LGMD1B)
- Peripheral neuropathy
- Autosomal recessive axonal Charcot–Marie–Tooth disease (AR-CMT2)
- Partial lipodystrophy syndromes
- Dunnigan type familial partial lipodystrophy (FPLD)
- Syndrome of lipoatrophy, insulin-resistant diabetes, disseminated leukomelanodermic papules, liver steatosis and cardiomyopathy (LIRLLC)
- MAD
Muscle, fat and bone cells all derive from mesenchymal cells, indicating that perhaps the lamins play an important role in the development, maintenance, or repair of this cell line.
Having so many distinct phenotypes arising from a simple gene supports the idea that lamins have multiple functions within the nuclear envelope.
Hutchinson-Gilford progeria syndrome 2004
THERAPY
There is currently no definitive therapy for HGPS but several potential strategies exist.
The restoration of the normal phenotype on a cellular level by the use of a morpholino provides hope for HGPS patients with the classical mutation,although many obstacles have to be passed.
Because of the dominant negative nature of the mutant lamin A protein, reversal of the cellular phenotype in HGPS cells requires the elimination of the mutant protein. Scaffidi and Misteli, to correct the aberrant splicing of the mutant LMNA pre-mRNA, designed a 25-mer morpholino oligonucleotide (exo11) complementary to the region containing the HGPS mutation in exon 11 to sterically block the activated cryptic splice site, thus preventing the access of the splicing machinery to the aberrant splice site.
Upon splicing correction, HGPS fibroblasts assume normal nuclear morphology, the aberrant nuclear distribution and cellular levels of lamina-associated proteins are rescued, defects in heterochromatin-specific histone modifications are corrected and proper expression of several misregulated genes is reestablished.
The reversibility of the cellular disease phenotype through correction of the aberrant splicing event may be used as a strategy for therapeutic purposes.
Reversal of the cellular phenotype in the premature aging disease Hutchinson–Gilford Progeria syndrome 2005
Viral vectors could be used to deliver antisense molecules to blood vessels such as the aorta and coronary arteries, the sites where they are needed most.
Short hairpin RNA (shRNA) constructs were designed to target the mutated pre-spliced or mature LMNAmRNAs. The shRNAs targeted to the mutated mRNA reduced the expression levels of Δ50 lamin A (lamin A isoform containing an internal deletion of 50 amino acids) to 26% or lower. The reduced expression was associated with amelioration of abnormal nuclear morphology, improvement of proliferative potential, and reduction in the numbers of senescent cells. These findings provide a rationale for potential gene therapy.
Correction of cellular phenotypes of Hutchinson–Gilford Progeria cells by RNA interference 2005
- Inhibition of farnesylation
Phase II Trial of Lonafarnib (a Farnesyltransferase Inhibitor) for Progeria
Lonafarnib is a farnesyltransferase inhibitor (FTI) that blocks the post-translational farnesylation of prelamin A and other proteins that are targets for farnesylation. Farnesylation is essential for the function of both mutant and non-mutant lamin A proteins, including progerin. Therefore, farnesyltransferase inhibitors are ideal candidates for treatment of HGPS.
Both cell culture and mouse model studies of HGPS demonstrate improved phenotype after exposure to FTI. In vitro, exposure of HGPS skin fibroblasts and progerin-transfected HeLa cells to FTIs, including lonafarnib, prevents preprogerin from intercalating into the nuclear membrane where it normally functions, and eliminates nuclear deformity. In vivo, three Progeria-like mouse models show no appreciable signs of toxicity after FTI administration. In all three of these models, disease is significantly reduced when compared to age-matched controls after oral administration of FTI.
Mark W. Kieran (Study chair) et al. propose that clinical features of HGPS can be ameliorated or reversed by blocking posttranslational farnesylation via treating patients with lonafarnib. They hypothesize that reduction of the quantity of functional progerin or, in the case of other progeroid laminopathies, other abnormal lamin proteins, will improve disease signs, symptoms and outcome. They also hypothesize that the toxicity profile of FTI inhibition using lonafarnib will be similar to that observed in children with malignant brain tumors treated with the compound.
However, even though FTIs have been proven safe and do not induce toxicity on the short term, accumulation of unfarnesylated progerin and prelamin A by blocking protein farnesylation may have undesired outcomes over a longer period of time. Indeed, cell-based experiments demonstrated that a subpopulation of cells expressing a variant of prelamin A that cannot be farnesylated over a period of several months display changes in nuclear morphology that are accompanied by reduced levels of the transcription factor. It is also important to point out that FTI treatment is preventing farnesylation of other cellular proteins, thus influencing other cellular processes including proliferation, apoptosis, differentiation, transcription, and immune response independently of prelamin A accumulation.
http://clinicaltrials.gov/
Hutchinson-Gilford progeria syndrome: review of the phenotype 2006
- Combined treatment with statins and aminobisphosphonates
Despite of in vivo benefit of FTI treatment described in Zmpste24-deficient mice (a progeria mouse model), further studies revealed that this treatment only produced a marginal (5%) reduction in prelamin A processing. This low effectiveness at the molecular level could be explained by an alternative prenylation of prelamin A by geranylgeranyltransferase type I under FTI treatment, as reported for other prenylated proteins such as K-Ras.
To address this hypothesis, Varela et al. tested the effect of FTIs, alone or in combination with geranylgeranyltransferase inhibitors (GGTIs), on prelamin A processing in human cells. This approach revealed a synergistic action of FTIs and GGTIs, suggesting that prelamin A can be geranylgeranylated in the setting of farnesyltransferase inhibition. Furthermore, the use of mass spectrometry analysis of prelamin A derived from FTI-treated Zmpste24-deficient fibroblasts and progerin derived from HGPS cells provided direct evidence that these proteins are alternatively geranylgeranylated when farnesylation is inhibited, which could explain the low efficiency of FTIs in ameliorating the phenotypes of progeroid mouse models.
Accelerated ageing: from mechanism to therapy through animal models 2009
Based on their observations, they hypothesized that the farnesylation of aberrant lamin A variants may also be targeted by drugs acting on the synthetic pathway of farnesyl pyrophosphate, a cosubstrate of farnesyltransferase and a precursor of geranylgeranyl pyrophosphate, the substrate of geranylgeranyltransferase I. Because statins and aminobisphosphonates are among the approved drugs used to block this metabolic pathway, they tested their effects both in vitro and in vivo. This therapy markedly improves the aging-like phenotypes of mice deficient in the metalloproteinase Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss and bone defects. Likewise, the longevity of these mice is substantially extended.
The molecular mechanisms through which this combined treatment with statins and aminobisphosphonates ameliorates age-related phenotypes probably involve the blocking of prelamin A prenylation. Statins inhibit hydroxymethylglutaryl coenzyme A reductase, an enzyme located at the apex of the mevalonate pathway, whereas aminobisphosphonates act on the last steps of the same synthetic pathway, inhibiting farnesyl pyrophosphate synthase and isopentenyl pyrophosphate isomerase. The observed additive or synergistic effect of statins and bisphosphonates on Zmpste24–/– aging-like phenotypes may derive from their sequential action on different enzymes of the mevalonate pathway, thereby blocking both protein farnesylation and geranylgeranylation and minimizing the possibility of alternative prenylation events that confer resistance to FTIs.
Thus, statins, widely used as lipid-lowering drugs, also inhibit the synthesis of cholesterol, have extensive immunomodulatory properties and target the proteasome degradation machinery, whereas aminobisphosphonates have strong antiosteoporotic properties and block angiogenesis through mechanisms that may be independent from their inhibitory actions on the mevalonate pathway. All of these pleiotropic effects of statins and aminobisphosphonates might contribute to an overall improvement in the health of Zmpste24–/– progeroid mice beyond the proposed action of these drugs in targeting the farnesylated forms of prelamin A that cause progeria. Nevertheless, many clinical studies have revealed that statins and aminobisphosphonates are well tolerated and are proven to be effective without showing any major negative effects after prolonged treatments. Furthermore, combinations of both compounds have been previously assayed in different in vitro and in vivo studies that have showed synergistic effects and no evidence of overlapping toxicities. The combined potential of these drugs as a therapeutic approach to slow down disease progression in children with progeria has lead to a recent clinical trial to test this combination of drugs for the treatment of progeria.
Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging 2008
