These diseases include neuropathies, muscular dystrophies, lipodystrophies, and premature aging diseases. 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.
Other health problems frequently associated with aging — such as arthritis, cataracts and increased cancer risk — typically do not develop as part of the course of progeria. Mayo Clinic does not endorse companies or products. Advertising revenue supports our not-for-profit mission.
This content does not have an English version. This content does not have an Arabic version. Overview Progeria pro-JEER-e-uh , also known as Hutchinson-Gilford syndrome, is an extremely rare, progressive genetic disorder that causes children to age rapidly, starting in their first two years of life. Request an Appointment at Mayo Clinic. Share on: Facebook Twitter. Show references National Library of Medicine. Hutchinson-Gilford progeria syndrome.
Genetics Home Reference. Accessed Feb. Learning about progeria. Frequency This condition is very rare; it is reported to occur in 1 in 4 million newborns worldwide. Inheritance Hutchinson-Gilford progeria syndrome is considered an autosomal dominant condition, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Research Studies from ClinicalTrials. Lamin a truncation in Hutchinson-Gilford progeria.
Epub Apr Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Genetics of aging, progeria and lamin disorders. Curr Opin Genet Dev. Epub Jul 6. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome.
It should be pointed out that two mutations in the LMNA gene result in another severe disorder called restrictive dermopathy RD [ 23 , 24 , 25 , 26 , 27 ]. This connection immediately points to major molecular pathways responsible for development of the disease phenotype, which develops when progerin permanently farnesylated, truncated lamin A is expressed from both alleles.
Mutations identified so far, beyond any doubts, are missense mutations affecting the head domain P4R coil 1B e. What is the current view of the molecular background of the disease phenotype development in HGPS progeria? Due to the complexity of interactions of lamins with signaling pathways and processes, it is difficult to point out only one or two major factors essential for the development of a particular phenotype. Indeed, a few such pathways have been discovered, and a few possible treatment strategies have been suggested.
For HGPS, it is not possible yet because we have to deal with not a simple, phenotypic null mutation, but a fully active protein with extra ability to associate with membranes with unknown efficiency and the possibility of relocating all possible interactions to the nuclear lamina [ 41 , 61 , 62 ].
The missing fragment of 50 amino acids from the C-terminus of progerin contains not only the target site for protease, but also has been suggested as a chromatin binding site [ 63 ] and encompasses several regulatory regions located in highly unstructured regions serine and glycine rich for phosphorylation by signaling kinases.
Due to the deletion, the progerin C-terminus amino acid residue sequence resembles the lamin B2 sequence. This, in turn, raises the question of whether progerin preferentially interacts with the B-type or A-type network. We might assume that progerin presence changes not only the mechanical properties of the entire cell nucleus and chromatin [ 64 , 65 ], but also the chromatin structure and division into the functional transcriptionally active domains TADs and structural lamina associated domains LADs , which in turn modify the gene regulatory mechanisms in differentiated tissue and most of all during development of tissues and organs.
Since lamins and interacting proteins play a regulatory role modulating signaling pathways and act as a hub integrating different signaling pathways, we may assume that progerin presence affects major regulatory pathways. Additionally, the direct link between chromatin and nuclear lamina structures with cytoskeleton and ECM should not be forgotten. Since progerin is predisposed to be located at the nuclear lamina and nuclear envelope, it might relocate all the interactions in which it participates, including with chromatin complexes and LADs , into the nuclear lamina or into the blebs specifically [ 74 , 75 ].
It should be pointed out that, in normal cells, a significant fraction of wt lamin A, specifically phosphorylated [ 54 , 76 , 77 , 78 ] is located in the nucleoplasm.
We might speculate that transcriptionally active lamin A-LADs are more prone to translocation to blebs [ 75 ]. On the other hand, previous studies reported that in HGPS cells in general, chromatin is converted into the heterochromatin-rich state and treatment reverses the blebbing and chromatin state [ 21 , 79 , 80 , 81 ] see also [ 82 ].
These controversies over chromatin state and transcription might be explained by differences in cellular models. Here arises another question regarding progerin and lamin skeletal structures.
It is well documented that A-type lamins and B-type lamins form separate networks in mammalian cells [ 36 ] and fly cells [ 83 ], but what is the preferential assembly partner for progerin if there is any? Some reports suggested that progerin copolymerizes with both A-type lamins and B-type lamins [ 84 ].
This discovery would nicely explain the controversies discussed above. Progerin due to the permanent farnesylation and carboxy methylation by isoprenylcysteine methyltransferase, ICMT may interact with the lamin B network at the nuclear envelope and still retains preference for polymerization to lamin A.
Apart from the C-terminal modifications and short deletion it is identical in sequence with lamin A. We will discuss potential consequences of the deletion further in following sections.
If we consider such simple relocation to the nuclear lamina of a particular, single LAD region we might predict that genes located in such a domain will be probably subjected to a different environment and be abnormally regulated e. We might speculate that these are only a few or limited number of genes and that there is a fair chance that the sister chromosome TAD will be still active in the old way. There is a fair chance to be bound by wt lamin A. However, what if is not?
What if we have, for example, 10 LADs relocated, or [ 87 ]? On top of that we have chromosome territories and domain organization for chromosomes different in each cell or even TADs on parent chromosomes are differently organized. Thus, relocation of TAD from the father chromosome may give rise to a different expression pattern than relocation of the same TAD from the mother chromosome [ 88 ].
In the above line of thoughts, we are trying to demonstrate only that the simplest possible mechanism of pathogenesis, which is relocation of a particular TAD to the nuclear lamina, may give rise to many different outcomes for a particular cell in question. This should also be kept in mind when considering therapeutic strategies. This means that design of an efficient therapy for HGPS cannot focus on particular pathways or processes, but would require progerin or prenylated mutant lamin A to be eliminated from patient cells as efficiently as possible.
This distinction has been made just to acknowledge the treatment option based on the idea of efficient elimination of prenylation of progerin or specific elimination of progerin itself.
The other lesson from our discussions might be the thesis that entire mechanisms associated with progeria should be studied in an animal model system when the presence of the mutation is subjected to different environmental conditions of particular tissues and long-term interactions being set and modified through the entire development. Therefore animal models and animal model studies are of extreme value to gain knowledge of the pathogenetic mechanisms of the HGPS and progeric laminopathies.
A number of mouse models for progeria have already been developed to investigate the molecular mechanism and potential treatment. They differ in genetic background and observed phenotype, but changes in nuclear shape are commonly observed. Changes in murine phenotype were observed only for homozygotes. The size and weight were reduced after four weeks of age and lifespan was shortened to 20 weeks, mostly probably due to dilated cardiomyopathy and heart failure. After two months of age, progressive loss of weight, and an abnormal posture characterized by hunched position and scoliosis were observed.
Mice had decreased blood glucose and serum triglyceride levels after four weeks of age, bigger hearts and kidneys, thinning of the ventricular wall and, in some cases, dilatation of both ventricles.
The immunohistochemical IHC analysis showed muscle degeneration foci, infiltration of inflammatory cells and interstitial fibrosis. At 16 weeks, some mice were losing their fur, whiskers and eyelashes. They completely lost the subcutaneous fat layer. The epidermis and hair follicles were atrophic and an increased number of apoptotic bodies in the basal layer of the epidermis and in hair follicles was observed [ 89 ].
Symptoms in heterozygotes were observed by 15 months of age—they were smaller than wild-type mice, appeared weak and lost hair.
Homozygotes were much smaller, muscle weakness was observed by six—eight weeks of age, they developed kyphosis of the spine, lost hair and appeared malnourished. The lifespan was longer than for the previous ZMPSTE24 model—mice were dying by six—seven months of age, probably mostly due to spontaneous bone fractures without healing, resulting in inability to eat. Prelamin A accumulation was also observed in MEFs, but no pathology was detected by IHC, especially no muscle degeneration or heart pathology [ 90 ].
A ZMPSTEdeficient model was also created using zebrafish, but no growth retardation was observed even for homozygotes, despite prelamin A accumulation [ 91 ]. Further models were focused on lamin. Yang and colleagues created a mouse model expressing progerin only by deletion of LMNA intron 10, the last nucleotides of exon 11 and intron Lamins A and C were not detected for homozygotes and were at the lower level than progerin for heterozygotes.
By six—eight weeks they began to lose weight and they died by about 27 weeks of age. Less subcutaneous fat and abdominal fat, kyphosis of the spine, osteolytic lesions, bone abnormalities e. They were very small, had no adipose tissue, micrognathia and an abnormal skull shape with open cranial structures, spontaneous bone fractures, misshapen MEF nuclei to a greater extent and died by three—four weeks of age [ 34 , 92 , 93 , 94 , 95 ].
It should be pointed out that LMNA -null mice had similar lifespan. Depending on mouse model, they died before birth [ 96 ] or 2—3 weeks after births [ 97 ] however the main observed symptom was muscle dysfunction. Interestingly, mice models with only prelamin A expression or lamin A only, did not show significant phenotype, similarly to the mouse model with lamin C only [ 98 ].
Other attempts were made to create tissue-specific models. Wang and colleagues developed transgenic mice expressing wild-type lamin or progerin in epidermis only, under control of a keratin 14 promoter. The minigene was tagged with FLAG and expressed at twice the endogenous lamin level. Mice had a normal growth rate and life span, with no alterations in skin, hair follicles or hair. However, for cultured primary epidermal keratinocytes with progerin overexpression nuclear shape alterations were detected [ 99 ].
Tissue-specific progerin expression was also obtained by Sagelius and colleagues using tetracycline-inducible mouse transgenic lines that carry a minigene of human LMNA , restricted to tissues expressing keratin 5. Wild-type lamin and progerin minigenes consisted of exons one—11, intron 11 and exon For progerin additionally the mutation c. Series of mice differing in expression levels were analyzed.
For some of them, hair thinning, growth retardation, premature death, abnormalities in the skin and teeth, fibrosis, and loss of hypodermal adipocytes were observed [ ]. Another mice model was generated by the same team and they analyzed the effect of progerin expression in preadipose and adipose cells. In long term up to 90 weeks this resulted in increased proliferation of progerin-expressing preadipocytes and adipocytes, accumulation of DNA damage, infiltration of macrophages followed by increased senescence of adipose tissue, progressive lipoatrophy, fibrosis and general inflammation [ ].
Thus, oxidative stress seems might be common feature in progeria since it has been also reported in patient fibroblasts [ 68 ] and provides another evidence for complexity of mechanism leading to phenotype development in HGPS.
Also models that introduce a point mutation into the LMNA gene were developed. Mounkes and colleagues created a mouse line with the LP mutation. In humans, presence of this substitution results in autosomal dominant EDMD, but in mouse progeria-like symptoms were observed and aberrant splicing between exons 9 and 10 was detected. They had a waddling gait suggesting immobility of joints , micrognathia and abnormal dentition, many skin symptoms such as hyperkeratosis or increased deposits of collagen, lack of the subcutaneous fat layer, decreased density of hair follicles, and decreased bone density.
Some degeneration of skeletal muscles and heart was also observed, but without typical dystrophic markers. For MEFs, discontinuities of the nuclear envelope, lamin C in cytoplasm, and shortened lifespan were observed [ ]. The first mouse model that directly reflects the most common HGPS mutation was created by Osorio and colleagues.
A point mutation c. GG and lamin C with no lamin A. GG mutation, it also results in cryptic splice site activation and progerin synthesis. Heterozygotes p. Additionally, nuclear abnormalities were observed.
Homozygotes p. An abnormal posture, marked curvature of the spine, loss of the principal fat deposits and subcutaneous fat layer, attrition of hair follicles, positive beta-galactosidase staining in lung and liver, involution of thymus and spleen, reduction in bone density with increased porosity, loss of vascular smooth muscle cells in the aortic arch, bradycardia, decrease in serum levels of glucose, IGF-1, insulin, leptin, growth hormone, and adiponectin were observed.
MEFs had large and abnormally shaped nuclei [ 13 , ]. The following two models represent a different perspective on progeria. Both ideas originated at a similar time but take advantage of the biological activity of different enzymes. This indicates that inhibition of ICMT might be a useful method for treatment of progeria. Another study tested compounds affecting progerin binding to lamin A in vitro and in a mouse model of progeria GG phenocopy mutation [ ].
Both cellular model parameters and mice life span were significantly improved. Chemical inhibition of NAT10 as well as its knockout in a progeria mouse model GG phenocopy significantly enhanced the lifespan of animals [ ].
Since NAT10 exhibits not only N-acetyltransferase activity but also other activities and functions, it is difficult to discuss potential therapeutic mechanisms [ , ]. Definitively, the level of progerin and other lamins seems to be unaffected. The authors suggested a mechanism based on improved nuclear transport as a major contributory pathway [ ], but there are still too many questions to be answered before we can seriously discuss potential mechanisms of NAT10 action in HGPS.
Many small molecule drugs for therapy of progeria have been tested so far. Only a few of them were tested in a mouse model system or during clinical trials. Most of the tested drugs were already studied earlier in other laminopathies and they address a particular selected signaling pathway or process. For example, to address the issue of abnormal gene regulation by progerin, a variety of histone deacetylase inhibitors such as trichostatin A, sulforaphane or butyrate have been used [ 81 , , ] in order to reverse the general gene repression trend.
In order to address cardiovascular problems, ERK kinase inhibitors were tested in laminopathies with cardiac phenotype, and they can possibly be used for amelioration of cardiovascular phenotype in progeria [ , ]. To address the issue of a high level of prenylated lamin A, farnesyl transferase inhibitors have been used together with drugs enhancing autophagy [ 80 , , ].
For a detailed review on the subject see: [ 13 , , , ]. Here we need to mention a small molecule approach targeted to inhibit carboxyl methyltransferase responsible for methylation of the cysteine residue in lamins with a CAAX motif [ 85 , ] and to use NAT10 inhibitors for laminopathies and specifically for progeria [ , , ].
We discussed these issues in detail in the Animal Models section. A separate question is how to properly define the critical disease markers and what markers can be used for proper assessment of the efficiency of a particular treatment procedure. Which set of markers is sufficient for cellular model studies and which sets are necessary for animal model studies? For tissue culture model studies several phenotypic markers of the disease have been used. RNAseq or any other means of gene expression profiling for controls and treatment have not been frequently used, but data gathered so far from these analyses are invaluable [ , ].
Due to such variety of treatment efficiency markers it is sometimes impossible to perform comparative analyses of phenotype improvement upon treatment, especially at the level of a tissue culture model system, especially when only one or few markers are analyzed such as nuclear blebbing, progerin level or proliferation rate.
Similarly, but on a smaller scale, due to the limited animal models available and studies performed, it is hard to compare the efficiency of treatment strategies in model systems. Interestingly, HGPS patient fibroblasts with the classical mutation show characteristic lobulated nuclei. This cellular phenotype is frequently used in cellular studies and animal model studies as a readily visible, obvious marker of the disease, and the efficiency of the treatment procedures.
Nuclear envelope lobulation can be reversed in such model cells by progerin silencing, inhibition of farnesylation, induction of autophagy, or a combination of them. The problem is that lobulation disappearance is not a valid method of analyses of improvement of the mechanisms at the molecular level. Similar lobulated nuclei can also be created by transfection of control fibroblasts with progerin protein and frequently prelamin A or lamin B but typically not by lamin A or lamin C proteins.
The major drawback of lobulated phenotype for monitoring efficiency of treatment is its superficial value. Such lobulated nuclei can also be created by overexpression of C-terminal lamin B fragments or other protein fragments containing a farnesylation motif [ ]. This suggests that it is more an issue of mechanical and sterical problems for the cell nucleus than it is really a functional one.
Interestingly, overexpression of lamin A in progeria fibroblasts does not improve the phenotype [ ]. Clinical trials of combined treatment with small molecules performed so far [ , , , ] demonstrated limited but statistically significant overall improvement of patients and statistically significant prolongation of lifespan but with probably limited potential for a further increase in efficiency.
The possible limitations are the therapeutic windows and dose limits for a particular drug, unknown contribution of a particular drug to the overall therapeutic effect, and possible lack of correlation or synergy between molecular effects of each drug administered at the same time point since in patient fibroblasts more efficient administration of drugs seems to be crucial [ ]. Several separate discoveries have made the consideration of gene therapy for HGPS possible.
Tissue culture model studies and then animal model studies revealed that if we block progerin expression, even together with lamin A expression, it is still beneficial compared to the starting disease model [ 34 , 98 , , , ]. The second discovery originated from the knowledge that human neuronal tissues are not affected by HGPS phenotype. The molecular background of this phenomenon was based on specific, epigenetic silencing of lamin A and progerin transcripts by microRNA.
The role of miR-9 and target sites in the lamin A-specific transcript was further confirmed by studies in animal models. The strongest silencing effect for lamin A transcripts was observed in the cerebral cortex and cerebellum [ 35 , 93 ].
This is in perfect agreement with the level of miR-9 in these tissues.
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