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Hutchinson-Gilford progeria syndrome otherwise known as Progeria (meaning prematurely old)(case study) or HGPS, is a severe genetic disorder. HGPS was initially reported in 1886 by Hutchinson and Gilford in England.(case) HGPS is extremely rare. The fact that there were only eighteen recorded cases between 1886 and 1945, will vouch for this argument.(case study) It is distinguished by a premature aging phenotype.(45) In fact significant, detailed research only began in the early 1990s. Hutchinson-Gilford progeria syndrome takes affect from early infancy (1 year old). In the first year, no significant abnormalities can be seen, however from the age of one year, abnormalities begin to occur. (Facts Progeria). HGPS is caused by an intermittent point mutation of the gene encoding for the nuclear lamin A, most frequently resulting in the expression of mutant lamin A (Lamin. &Alterations & Case).
The Lamin Genes
Lamin A- & B- types are intermediate filament proteins that have a huge structural role in the nuclear lamina. The nuclear lamina forms an interface between the inner membrane of the nucleus and the chromatin contents of the nucleus. There are two foremost isoforms of the A- type lamins, lamin A and lamin C. They originate from a single LMNA gene being alternatively spliced, followed by transcription and translation. (mutant Lamin)
The Lamin A gene consists of 12 exons. It covers close to 25,000 bases of
genomic DNA. Exons 1-12 code for lamin A. Exons 1- 10 code for lamin C.(Nature bookmark)
There are two B-type lamin genes. These are LMNB1 and LMNB2. LMNB1 encodes a single protein, lamin B1 protein. Similarly to the LMNA gene, LMNB2 is also alternatively spliced and thus encodes two proteins, lamin B2 and lamin B3. B-type lamins are expressed continuously as a person develops. At least one B-type lamin is present in every cell type. Lamins have a significant role in the functions of the nucleus, particularly in shape. They also have huge roles in the replication of DNA and transcription of RNA in the ribosome. (mutant Lamin)
After being translated, Lamins A and B are modified at their carboxyl-terminal -CaaX (C= Cysteine, a= aliphatic, X= an Amino acid). These consist of consecutive farnesylation of the cysteine in the C- terminal CaaX design. The aaX now left is a tripeptide. Proteolytic cleavage of the aaX follows. This involves the breaking of peptide bonds between amino acids in proteins (http://www.clcbio.com/index.php?id=42). A methyl group is also added to the faresylated Cysteine. Lamin B remains permanently farnesylated. This is not the same for lamin A(at this stage is prelamin A). Prelamin A is immature lamin A. It goes through a second cleavage in order to mature. The enzyme responsible for this is zinc metalloproteinase ZMSPTE24. (Mutant Lamin)
People with HGPS lack functional ZMSPTE24. In most cases there is a mutation on exon 11 of chromosome 1. There is a single base substitution that occurs in the body and is not inherited. This is G608G (GGC > GGT). This mutation creates a new splice site within exon 11 for the LMNA gene. This causes 50 amino acids to be deleted from the prelamin A near the C=O terminus. This disrupts the proteolytic cleavage, and means the prelamin cannot mature properly, and instead becomes truncated. This is in some way, surprising that this specific substitution happens in more than 95% of cases. However when one considers the fact that the nucleotide substitution is from cytosine (C) to thymine (T), keeping in mind that a methylated C can quite easily become deaminated to T, the mutation makes more sense. (Nature Bookmark)
( Scaffidi P, Gordon L, Misteli T (2005) The Cell Nucleus and Aging: Tantalizing Clues and Hopeful Promises. PLoS Biol 3(11): e395. doi:10.1371/journal.pbio.0030395)
De novo mutation in exon 11 of LMNA gene accounting for molecular basis of HGPS.
Even though the gene is mutated a protein is still produced. However the second ZMPSTE24 cleavage site is gone. This creates a mutant prelamin A protein known as progerin. This progerin accumulates and seize repair and replication factors. This causes delayed replication forks. This disintegrates into DNA double strand breaks also known as DSBs. This causes genomic instability. The genetic deficiency in DNA repair creates an increased sensitivity to DNA damage. Checkpoints being activated in the cell cycle stalls the cycle, giving it time to repair the damage before continuing. In this case, the checkpoints are controlled by ATM and partially ATR, both kinases. ATM activates in response to DSBs and structural interferences in chromatin. ATM can cause the cell cycle to stop by phosphorylating downstream targets. The continual activation of this kinase checkpoint in HGPS causes a delay in DNA repair efficiency.( Bakkenist, CJ; Kastan, MB. (2003). "DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation". Nature 421 (6922): 499-506) (Pre Lamin)(Alterations)
HGPS is said to be autosomally dominant. This means parents who do not suffer with HGPS will not pass it on to their progeny. When one considers the short life span of a HGPS patient, it seems implausible, if not impossible for the patient to have children.( http://www.healthline.com/galecontent/progeria-syndrome-1?print=true) However in stark opposition to this argument is the case of the Kahn family, who BBC famously made a documentary about. The Kahn family had 4 children born with HGPS along with two healthy children. Upon studies of the family, it was noted that, in this case, the disorder was recessive and inherited. This means both parents carried the gene for mutated lamin A. This is baffling, when one considers the fact that every other case in the world reported to date, does not show this. There has never been another case where there was more than one member of the family with HGPS. Obviously there is still much to be learned about HGPS(BBC).
The phenotype of HGPS patients is very distinct. In the early days of discovery the only way of determining if a patient had this disorder was to examine the patients phenotype i.e. the patient was examined on his/her appearance. In a way it is as if the HGPS phenotype mimics the phenotype of a much older generation. In a study done by "The New England Journal of Medicine," published in "february 7, 2008" the phenotype of typical HGPS patients was established. 15 HGPS patients were examined, ranging from 3.5 months to 4 years of age. All patients appeared older than their age. Skin abnormalities were found in all 15 patients. Alopecia (hair loss) was found in 13 patients. 11 patients slept with their eyes open. 9 patients exhibited cyanosis around their mouth, which causes the mucus membranes and skin to have a blue/black colour(http://www.wrongdiagnosis.com/symptoms/ear_blueness/book-causes-13a.htm). 8 of the 15 displayed outstanding scalp veins, a feature of most elderly people. 7 of the 15 did not have a full range of motion in their joints, also associated with the elderly. 15 of the patients were heterozygous for the substitution of the cytosine by thymine, in the LMNA gene. All children displayed "prominent cuntaneous vasculature" and "fingertip tufting" (Phenotype).
Other typical features in HGPS patients are undersized face/jaw in comparison to head size, and relentless cardiovascular disease. In fact, astonishingly many HGPS patients (who are children) undergo heart surgery. However, most HGPS patients die due to these cardiovascular problems. It is interesting to note that the phenotype is not apparent in HGPS patients during their first year of life. However after this the phenotype becomes apparent. (Facts Progeria)Also, HGPS patients are, mentally, age appropriate. There is no symptoms of Alzheimer's or Parkinson's disease, or anything akin to mental illness associated with elderly people. Mentally, HGPS patients still have the mindset of a child.(BBC & Facts progeria)
There have been some interesting developments in the treatment for HGPS recently. The best possible avenue of treatment seems to be the use of a Farnesyl transferase inhibitor (FTI), an antineoplastic drug. As previously mentioned, the farnesylation/cleavage processes of the lamin A is disrupted in HGPS. A farnesyl group acts as an anchor for the lamin A. It holds the protein in place, but is then removed when the protein is in place i.e. embedded in the nuclear lamina. HGPS patients cannot complete the process appropriately and mutant form of an immature lamin A, prelamin A, (progerin) is the consequence. A build up of this progerin in the nuclear membrane has been proven to cause accelerated aging. (Treatment) Therefore inhibiting the farnesylation of protein theoretically should improve the abnormal nuclear morphology and appearance in cellular and animal samples of HGPS. (Treatment 2)
The ZMPSTE24 endoproteolytic site is within the 50 amino acid deletion in the lamin A mutation. This means there is no site for the ZMPSTE24 enzyme to work appropriately. Therefore the progerin keeps its farnesylated carboxymethylated cysteine at the carboxy terminal. FTIs are chemical inhibitors. They have been proven to overturn nuclear membrane abnormalities in cells that have the mutant lamin A. This has mostly been tested on mice with the induced mutation or who lack ZMPSTE24. Even though multiple sources have shown that HGPS' root cause lies in the farnesylated progerin, the actual mechanism of how it causes the syndrome is yet to be discovered. Genome- wide expression studies on human HGPS cells have been done in order to identify the alterations of functional groups of genes that characterize faulty signalling pathways, and also to determine the affect of FTIs on this.
Although the FTIs look promising, there seems to be no treatment for HGPS at this moment in time. All FTIs articles I have researched have not made a biopharmaceutical drug suitable for HGPS. However as HGPS patients symptoms include aching joints and cardiovascular problems, along with many more common in elderly people, then clearly some of the symptoms are treatable. I deduce from the fact that elderly people have medication for their problems as they get older, for exam ple high blood pressure, aching joints etc., so then HGPS patients will also be available for this symptomatic treatment. Also, as said above many HGPS patients undergo heart operations in order to reduce the chances of cardiovascular disease.
Recently I have being learning of gene therapy. This could offer some sort of treatment for HGPS in the near future. Gene therapy is a new concept on medicine. Gene therapy actually targets the defective gene and replaces t with an effective copy. Somatic gene therapy would be for patients who are living with a genetic disorder. In the case of HGPS, this would not be very efficient as every cell is affected. However germline gene therapy could be a more effective alternative. This technique targets the genes in gametes, this way preventing the mutation from being passed on.(Human Gene) Even though most studies have shown the mutation is in fact sporadic and not hereditary, there was the Kahn family, mentioned above, who opposed physically this argument. As there is still much to learn from HGPS, this could be a future avenue of treatment, only time will tell!
HGPS and normal aging:
As the understanding of HGPS and other laminopathy diseases increased, links have been made to aging and laminopathy diseases. There is evidence for these links. Firstly, the mechanism that causes HGPS is also active in normal aging cells, just to a much lower extent. Also, Healthy people express low amounts of progerin from this erratic use of the cryptic splice site in their cells. This results in similar phenotypes. DNA damage accumulation is not caused by a deficiency in DNA repair in HGPS, this is also the case for healthy aging cells. Finally, DSBs that occur due to aging are not repaired. This is interesting as DSBs that are caused by genotoxins in the same cells can be effectively repaired. This is very similar to HGPS cells. All these comparisons support the linkage between natural human aging and HGPS. Laminopathy diseases could possibly become the foremost model used in the study of human aging.(Pre lamin)
In conclusion, The LMNA gene causes the production of the protein lamin A. This is essential in the nuclear envelope structure and thus the nucleus structure and function. A heterozygous base substitution within LMNA gene on exon 11, of chromosome 1 causes the production of mutant Lamin A. An immature form of lamin A. This means they lack mature lamin A. This has devastating causes on nuclear organisation, chromatin attachment and DNA repair. This lack of this ZMSPTE24 enzyme causing DNA repair complications, may be reason for the accelerated aging in HGPS, however this has not been conclusively proven. (Lamin Aging) The accumulation of progerin in cells causes genomic instability. The cell cycle is stalled by kinases and this causes disruptions in DNA repair. HGPS and other laminopathy disease cells have many similarities with normal aging cells. This means HGPS and other laminopathy diseases can be closely related to the study of normal human aging. Apart from the incredible exception of the Kahn family, HGPS is an autosomally dominant syndrome caused by a sporadic mutation. The syndrome exhibits a very specific phenotype. A phenotype that makes them appear a lot older than actually is the case. However, HGPS patients have appropriate intelligence i.e. HGPS does not affect the mentality of the patient. Treatment wise, there is nothing specific for to prevent the HGPS mutation. However, some of the symptoms can be treated separately. As there is still much to learn about HGPS the avenues of attack for medication are still very open. But, in this new era of biopharmaceutical focus, FTIs look promising, along with some derivative type of gene therapy.