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Studying the Molecular Mechanism of Post-Translational Modification of Lamin A in Hutchinson-Gilford Progeria Syndrome

Tyler Kaplan 
Department of Biology 
Lake Forest College 
Lake Forest, IL 60045



Hutchinson-Gilford Progeria Syndrome (HGPS) is a genetic condition that presents itself as premature aging. It is caused by a point mutation in exon eleven of the LMNA gene. This gene is responsible for producing lamin A and lamin C proteins. The point mutation is a silent mutation that causes the splicing pattern of LMNA to be altered resulting in a mutant protein called progerin to form. The build-up of this protein causes HGPS. One area of research is the usage of farnesyltransferase inhibitors (FTIs), which block a step in the post-translational modification of lamin A to prevent the build-up of progerin on the nuclear envelope. To study FTIs, researchers have utilized a series of transgenic mice and an arsenal of molecular biology techniques. In this paper, I propose the usage of a novel transgenic mouse that can be utilized to further study the molecular mechanism of lamin A synthesis and FTI usage. FTIs help alleviate the symptoms of afflicted children and hopefully can be utilized in the future as a cure.

Hutchinson-Gilford Progeria Syndrome Phenotype

The ultimate goal of molecular biology is to achieve an understanding of genetics such that aging can be prevented. However difficult this undertaking may sound, scientists can study a condition where the aging process is accelerated. This may provide some valuable insight into the mechanisms of aging and allow the process to be reversed. Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare disorder where aging occurs prematurely (Arancio, Pizzolanti, Genovese, Pitrone, & Giordano, 2014). The condition is caused by a mutation in LMNA, which is crucial for stabilizing the structure of a cell (Arancio et al., 2014). Unfortunately, this condition is always fatal and currently lacks a cure. Hopefully, through understanding the molecular basis of the condition and its mechanism of action, steps can be taken towards the development of a cure.

Individuals afflicted with HGPS exhibit symptoms that resemble the elderly. HGPS was named after two physicians who described symptoms of the condition independently. Dr. Jonathan Hutchinson first identified the condition in 1886, while Dr. Hastings Gilford described the condition in 1897 (“Hutchinson-Gilford Progeria Syndrome,” 2014). The condition is incredibly rare and is estimated to occur in 1 in 8 million births (“Hutchinson-Gilford Progeria Syndrome,” 2014). Affected children appear normal at birth, but their health rapidly declines within their first year of life. The condition currently has no cure or medications to slow the progression of the disorder. The average life expectancy of an affected person is thirteen years. However based upon the progression of the illness, the range of life expectancy is typically between six and twenty years (Gordon, Brown, Collins, 2003).

Hutchinson-Gilford Progeria Syndrome causes a variety of physical ailments. Within the first three years of life, baldness occurs. This often extends to the loss of eyebrows and, in some cases, eyelashes as well. Afflicted individuals also exhibit stunted growth. Patients present with short stature, low weight, and below average weight to height ratio. These measurements are quantified by people affected being below the third percentile in both height and weight (Gordon, 2003). Growth hormone is often prescribed to help improve weight and growth (Shah, 2013). Weight is low partially due to low bone density, thus individuals are at risk for bone breakages and fractures. Arthritis often develops as well, which is due to the degeneration of cartilage. Cartilage is at the ends of bones and acts as a lubricant between bones. It is recommended that affected individuals live an active lifestyle and undergo continuous physical therapy to reduce arthritis symptoms and to improve joint mobility (Shah, 2013). HGPS individuals have a head that is disproportionately large for their face and have a high-pitched voice. These symptoms are unique to HGPS.

Many HGPS symptoms are typically seen in the elderly. One of these symptoms is the loss of subcutaneous fat to such low levels that individuals exhibit prominent veins over most of the body including the head (Gordon 2003). Due to low levels of fat, leptin concentration in the blood is abnormally low. Leptin is a hormone secreted by fat cells that helps indicate when an individual has eaten enough (Gordon 2003). Interestingly, half of HGPS cases show signs of insulin resistance without the onset of diabetes; thus insulin is sometimes required before meals (Gordon 2003). Skin and nails are often dry in HGPS patients. Dryness of the nails causes them to be brittle, and thus crack easily. This can prevent nails from growing normally. In addition, a condition known as circumoral cyanosis develops. This is where the skin has a blue-purple coloration because tissues near the surface of the skin do not receive enough oxygen (“Cyanosis in children,” 2014). Therefore, most of the blood received by these tissues is not oxygenated and thus the blood is not its typical scarlet color. Although the abnormal features of HGPS are problematic, the major health issues of affected individuals are due to the failure of other organ systems.

Cardiovascular disease is the most prominent symptom that develops in afflicted persons and is the most common cause of death. Atherosclerosis, the hardening of the arteries due to plaque buildup, develops which causes a variety of cardiovascular problems. Hardening arteries are problematic because it results in elevated blood pressure, whereas normal elastic arteries help maintain a lower blood pressure. As cardiovascular disease develops, individuals usually develop hypertension (high blood pressure) (Gordon 2003). As a result of plaque buildup, arteries are narrower than normal and blood flow is partially restricted. Organs are supplied an inadequate amount of oxygen, forcing the heart to compensate by working harder than it normally should.

The onset of atherosclerosis can cause cardiac events before the age of five (Gordon 2003). This includes heart attacks, strokes, congestive heart failure and angina. A stroke occurs when blood flow to the brain is disrupted, thus brain cells are unable to receive oxygen. Strokes are often caused by blockage of the carotid artery, the main artery that supplies blood to the brain. Strokes can also lead to physical and cognitive decline based upon which area of the brain is damaged (Gordon 2003). Congestive heart failure is the weakening of the heart muscle, causing it to pump blood less effectively. Congestive heart failure occurs as a result of elevated blood pressure and plaque build-up in the coronary arteries, which provide blood to the heart. In addition, blockage of the coronary arteries can lead to angina, which is pain in the chest due to the heart’s oxygen demands not being met (Gordon 2003). Death is often a result of a heart attack or stroke before the age of twenty (Gordon 2003). Although no treatments are currently available, medication is often taken to help slow down the progression of cardiovascular disease. Nitroglycerin is prescribed to lessen the symptoms of angina, and anticoagulants are taken to help slow plaque buildup (Podrid, 2014)(Gordon, 2003). In addition, there are a variety of medications that are being developed to help slow the progression of the illness.

Medications are being tested to alleviate some of the detrimental symptoms of HGPS. There is a special medicinal cocktail that can be utilized to help lessen the effects of some of the symptoms. Pravastatin is utilized to help slow the progression of atherosclerosis. Zoledronic acid is utilized to increase bone density in order to effectively combat the typically low bone density observed in HGPS patients. In addition, farnesyltransferase inhibitors (FTIs) are utilized to block part of a biochemical pathway that is responsible for anchoring lamin A to the nuclear membrane. This pathway will be described later in the paper (Shah, 2013). The FTI utilized is Lonafarnib, which was originally designed as a cancer medication. However, patients taking Lonafarnib have shown improvements of symptoms which include weight gain, improved bone density, increased hearing, and increased elasticity of blood vessels as well (“Progeria clinical trials,” 2014). Therefore, Lonafarnib can be beneficial in extending the lives of HGPS patients since heart attacks and strokes are the typical cause of death in HGPS. Although the observed ramifications of HGPS are detrimental to an individual, it is crucial to understand the molecular mechanism that is responsible in order to properly treat it.

Molecular Function of LMNA

The phenotypic consequences of HGPS are all caused by a point mutation in the LMNA gene. LMNA codes for lamin A and lamin C, which are intermediate filaments crucial for maintaining nuclear stability by making up the meshwork of the nuclear lamina (Davies et al., 2011) (Arancio et al., 2014). Lamin A and C are splice variants of the LMNA gene. Therefore, both proteins can be produced from the same gene based upon the splicing pattern when mRNA is being matured. The mutation is classi

fied as a “de novo” mutation where the mutation is received without either parent having the point mutation. However, it is unclear when this mutation occurs. HGPS is an autosomal dominant condition, thus only one mutant LMNA allele is necessary for the condition (“Hutchinson-Gilford Progeria Syndrome,” 2014). The mutation is a silent mutation in exon eleven of the LMNA gene on chromosome one. A silent mutation is a point mutation in the genome, but the amino acid sequence is not altered. Therefore, change of a cytosine to a thymine in exon eleven results in glycine remaining as the amino acid in the primary structure of lamin A. However, the silent mutation alters the splicing pattern of the LMNA gene where an additional gene product is produced known as a progerin (Gordon 2003). The activation of this splice variant results in the deletion of fifty amino acids from the C-terminal end of the protein. This causes an abnormal immature lamin A protein to be produced since the protein cannot undergo post-translation modifications due to the fifty amino acid deletion (Gordon 2003). Therefore, the silent mutation prevents the proper synthesis of lamin A since the mature protein is unable to be produced (“Hutchinson-Gilford Progeria Syndrome,” 2014).

Four post-translational steps are required to produce mature lamin A. Immature lamin A is called pre-lamin A. First, a farnesyl group is added on to a cysteine containing motif on the C-terminal end of the protein. Once the farnesyl group is added to the cysteine, the three C-terminal amino acids are cleaved so cysteine is the C-terminal amino acid. The farneysl group at the C-terminal end binds to the nuclear envelope thus anchoring lamin A to the nuclear envelope as well(“Hutchinson-Gilford Progeria Syndrome,” 2014). A farnesylation reaction is a type of alkylation where a fifteen carbon group, a farnesyl group, is added to a cysteine residue in a protein (Schaller, 2014). This group acts as a hydrophobic tail facilitating the binding of lamin A to the non-polar nuclear membrane (Schaller, 2014). Metallopeptidase Zmpste24, an endoprotease, removes an eighteen amino acid peptide from the C-terminal end. This removes the farnesyl group from pre-lamin A, releasing lamin A from the nuclear membrane. Once these modifications occur, a mature lamin A is produced (Gordon 2003)(“Hutchinson-Gilford Progeria Syndrome,” 2014). However, when an individual receives the silent mutation that causes HGPS, pre-lamin A has a fifty amino acid deletion near the C-terminal end of the protein, which alters the structure of the protein such that metallopeptidase Zmpste24 is unable to bind to pre-lamin A to cleave the protein and remove the farnesyl group (Gordon 2003). Thus, pre-lamin A remains bound to the nuclear membrane and is intercalated into the inner nuclear membrane, which over time disrupts the structure of the nucleus due to the additional stress added to the nuclear membrane from the accumulation of progerin (Gordon 2003). Abnormal lamin A proteins are called progerins. Immunofluorescence has been utilized to view the nuclei of HGPS fibroblasts. In 40-50% of cells, the nucleus exhibits an abnormal shape due to progerin accumulation in the nuclear membrane (Gordon 2003). Fortunately, mouse models are being utilized to study the condition in great detail.

Multiple mouse models are currently in use to better understand the molecular mechanisms of HGPS. Mice are a useful model organism because their biology is very similar to that of humans. Often, mice exhibit nearly identical symptoms to humans when utilized as a model organism for a condition. One major area of study is the usage of farnesyltransferase inhibitors, which are proteins that prevent farnesyl groups from being added when a protein is being modified after translation. In particular, FTIs to prevent the addition of a farnesyl group onto lamin A is being tested (Yang et al., 2011). As mentioned earlier, progerin (mutant lamin A), has a fifty amino acid deletion in the C-terminal region of the protein whereby the protein structure is altered such that the enzyme (Zmpste24) responsible for removing the farnesyl group from lamin A is unable to do so. Since the structure of lamin A is altered, it is unable to bind to the highly specific active site of the enzyme. Lamin A remains bound to the nuclear membrane when the farnesyl group cannot be cleaved, thus causing lamin A to accumulate on the nuclear membrane. FTIs circumvent this problem, whereby if lamin A is unable to be farnesylated, it will not become anchored to the nuclear membrane (L. G. Fong et al., 2009). In theory, many of the phenotypic consequences of the nuclear accumulation of lamin A should be ameliorated.

A series of mouse models have been utilized to further study how FTIs could be a potential treatment for HGPS. One mouse (LMNA(HG/+)) is a HGPS knock-in mouse, where the mice are heterozygous for the human mutation in exon eleven of LMNA that results in HGPS. Thus, these mice have HGPS. An additional knock-in mouse (LMNA(nHG/+)) was utilized that had the C-terminus –CSIM motif changed to –SSIM meaning that a cysteine residue was changed to a serine residue (Yang et al., 2010). This was done because serine and cysteine have very similar R groups differing by cysteine having a sulfur where serine has an oxygen atom. Thus, the proteins conformation remained similar, but it could not be farnesylated. Finally, a knock-in mouse was generated (LMNA(csmHG)) where its lamin A protein cannot be farnesylated since its C-terminal was altered so it did not contain an isoleucine. Therefore, the wild-type CSIM motif was changed to just a CSM motif at the carboxyl terminal. However, this mouse still contained the HGPS mutation (Yang et al., 2011). The mice whose lamin A could not be farnesylated were utilized to study how FTIs could potentially be employed to help treat HGPS patients. LMNA(HG/+) mice exhibit a phenotype very similar to that of humans afflicted with HGPS. The nuclei of these mice exhibit nuclear blebbing. They have significantly lower body weight than wild-type mice, have less adipose tissue, and shorter life expectancies (Yang et al., 2010)

Additionally, LMNA(HG/+) mice had more rib fractures and lower bone density which essentially mimics the early-onset osteoporosis observed in human HGPS individuals (Yang et al., 2010). However, these symptoms were not eliminated in LMNA(nHG/nHG) mice that only contained lamin A proteins which were not farnesylated (Yang et al., 2011). This was surprising since previous research showed FTIs had been effective (L. G. Fong et al., 2009). Thus, the LMNACSM mouse was developed in response to these disappointing results since the researches believed the cysteine to serine amino acid substitution could have had a deleterious effect (Yang et al., 2011). Also, the symptoms of these mice were milder than that of the LMNA(Hg/+), indicating the inability for lamin A to be farnesylated was beneficial. Interestingly, both the LMNA(csm/csm) and the LMNA(csm/+) mice exhibited phenotypes that were statistically similar to that of wild-type mice. Amazingly, the LMNA(csm/csm), which only produces progerin and no lamin A or lamin C, lacked the symptoms that are common in HGPS. This indicates that the accumulation of lamin A to the nucleus is a more important factor than the altered structure of progerin. Adipose tissue, body weight, survival rate, and bone density were all indistinguishable from that of wild-type mice. Nuclear architectural abnormalities were also lower in the LMNA(csm) mice than mice with a mutation causing HGPS (Davies et al., 2011; Yang et al., 2011). This indicates that the mutation introduced has a drastic effect on the symptoms observed in mice. The results received from FTIs were so promising that human trials have been conducted.

Preliminary FTI trials have been tested in humans to determine if it can extend the lifespan of afflicted individuals. The drug Lonafarib was utilized in the trial, which reversibly binds to the active site of a farnesyltransferase where the CSIM motif typically binds so the cysteine residue can be farnesylated (L. G. Fong et al., 2009; Gordon et al., 2012). Thus, competitively inhibiting this enzyme should prevent pre-lamin A from being farnesylated and prevent progerin from accumulating on the nuclear envelope (Gordon et al., 2012). The results of the study were promising since every patient showed an improvement in at least one of the symptoms caused by HGPS. Lonafarib improved cardiovascular disease in patients as demonstrated by improved vascular elasticity (Gordon et al., 2012). This is crucial because cardiovascular disease is typically the cause of death of HGPS patients. Although Lonafarib is not a cure, it is a valuable first step towards treating individuals with HGPS by helping to alleviate symptoms and improving quality of life. Although altering the primary structure of lamin A provides strong evidence for the potential usages of FTIs, it is important to also study the phenotypic consequences of eliminating the enzyme that is crucial for lamin A maturation.

Zmpste24 deficient mice exhibit HGPS like symptoms. Zmpste24 is an organometallic protein that is required for the maturation of pre-lamin A to lamin A(L. G. Fong et al., 2009). The enzyme cleaves the CSIM motif at the C-terminal end of lamin A. The farnesyl group is covalently bonded to the nucleophillic sulfur of the cysteine and is also removed in the final processing steps of lamin A. Zmpste24 knockoutmice have been designed (Zmpste24-/-) to test the ramifications of this mutation (Loren G. Fong et al., 2004). Initially, mice appear normal but quickly exhibit symptoms similar to humans afflicted with HGPS, such as osteoporosis, alopecia, and slowed growth in comparison to wild-type mice (Loren G. Fong et al., 2004).

Pre-lamin A accumulates on the nuclear envelope since no enzyme is present to perform the post-translation modifications and the nuclear architecture becomes deformed (Loren G. Fong et al., 2004). However, Zmpste24 knockouts that were heterozygous for the LMNA gene (Zmpste24(-/-)LMNA(+/-)) greatly reduced the symptoms seen in the Zmp

ste24 knockouts. This indicates that there is a dose dependent relationship between lamin A accumulation on the nuclear envelope and the severity of the symptoms observed. Although Zmpste24 is crucial for lamin A processing, lamin A accumulation on the nuclear envelope is the major factor influencing the spectrum of the phenotypic consequences observed. In addition, mice that could only produce lamin C, a splice variant of lamin A, exhibited normal development and life expectancy in comparison to wild-type mice (Osorio et al., 2011).

Mice that directly synthesize mature lamin A were studied to further test the importance of the post-translation modification of lamin A (Coffinier et al., 2010). This was done by creating transgenic mice that contained a stop codon immediately after the last amino acid codon for mature lamin A. Thus, a missense mutation was inserted into the LMNA gene to bypass the processing steps typically required for lamin A synthesis (Coffinier et al., 2010). It is important to note that these mice LMNA(LAO/LAO)produced the same amount of lamin A as wild-type mice. Previous research suggested pre-lamin A modifications to mature lamin A were required to deliver lamin A to the nuclear rim to serve its role in the nuclear lamina. However, mice that directly synthesized lamin A displayed no diseased phenotypes indicating a different process is involved in delivering lamin A to the nucleus(Coffinier et al., 2010). LMNA(LAO/LAO) mice lacked nuclear abnormalities present in HGPS mice and its lamin A was properly oriented in the nucleus. This research supports research done by Fong, where LMNA(LAO/+)Zmpste24(-/-) mice had significantly lower levels of pre-lamin A accumulation on the nuclear envelope, strengthening the argument of a dose-dependent relationship between pre-lamin A accumulation and symptom severity (Coffinier et al., 2010; Loren G. Fong et al., 2004). Future research can take this study further through the generation of a new transgenic mouse to develop a deeper understanding of Zmpste24.

Experimental Proposal

A double mutant mouse could provide additional information about the molecular mechanisms of lamin A synthesis. One study demonstrated Zmpste24 knockout mice exhibit HGPS like symptoms most likely due to the accumulation of pre-lamin A on the nuclear envelope (Loren G. Fong et al., 2004). Additionally, a transgenic mouse that directly synthesizes mature lamin A does not exhibit any diseased phenotypes and is statistically indistinguishable from a wild-type mouse in a variety of quantitative health measurements (Coffinier et al., 2010). Thus, it would be beneficial to create a mouse that contains both of these mutations in order to study the phenotypic consequences of this double mutation. This transgenic mouse would be Zmpste24(-/-) and LMNA(LAO/LAO) and would therefore lack the enzyme that cleaves the CSIM motif which includes the farnesyl group from the carboxyl terminal, but directly synthesizes mature lamin A thus bypassing post-translation modification of lamin A. Since LMNA(LAO/LAO) mice are phenotypically normal, the phenotypic consequences of the double mutant mice will most likely be linked to the Zmpste24 knockout. This experiment could elucidate secondary functions of Zmpste24 since lamin A does not require Zmpste24 to become fully functional. However, due to the specificity of the active site of most enzymes, Zmpste24 most likely is only required to cleave pre-lamin A. Thus, I hypothesize Zmpste24(-/-)LMNA(LAO/LAO) will be phenotypically normal and statistically indistinguishable in comparison to wild-type mice. A positive control will be wild-type mice which will be utilized as a baseline for the typical phenotype of a mouse. These mice must be homozygous for the normal LMNA allele (LMNA(+/+)) and homozygous for the gene that codes for normal Zmpste24 (Zmpste24(+/+)). A negative control will be the Zmpste24 knockout mouse because it will provide data from mice with symptoms consistent with HGPS. These controls will be crucial to the experiment and provide mice to compare with the experimental double mutant transgenic mice.

The double mutant mouse model is utilizing previous research on the effects of single gene mutations of the Zmpste24 enzyme and LMNA. The most crucial part of preparing for this experiment is the generation of the novel transgenic mouse. This can be done relatively easily by receiving Zmpste24(-/-)and LMNA(LAO/LAO) mice from the labs that first generated them. Since both of these mice are homozygous for their mutations, breeding both of these mutants will result in all of their offspring being homozygous for both of the mutations of interest. However, this still must be genotypically confirmed through polymerase chain reaction (PCR). To confirm the Zmpste24 mutation, primers were previously designed that can distinguish between the wild-type Zmpste24 allele and the mutant allele (Loren G. Fong et al., 2004). The mutant PCR product produces a product that is 240 base pairs, while the wild-type product is 320 bp. Therefore, one can confirm the mouse is homozygous for the Zmpste24 mutant allele if the primers produce a single band at 240 bp. However, if two bands are produced at 320 bp and 240 bp respectively, then the mouse is heterozygous for the mutation. An EcoR1 digest will be utilized to confirm the mouse is also LMNA(LAO/LAO) because the vector is flanked by EcoR1 sites. The products of the EcoR1 digest can then be run on a gel for confirmation of the mutant. The wild-type product will produce a band that is 10.4 kb, while the mutant allele should produce a band that is 9.4 kb. Thus, mice homozygous for the LAO allele should only produce one distinct band at 9.4 kb (Coffinier et al., 2010). The PCR products of both mutant alleles will also be sequenced for further confirmation. However, the sequencing is not necessary since the sequences were previously verified.

The mutation must be checked for its functionality. Western blotting will be utilized to determine which proteins are being produced. Antibodies that bind specifically to lamin A have been previously designed. Thus, to ensure that the Zmpste24 is truly eliminated, the presence of a pre-lamin A band in western blot indicates mature lamin A is not being effectively modified post-translation. The pre-lamin A antibody can be utilized as an effective negative control for the LAO transgenic mouse because it directly synthesizes mature lamin A, thus no pre-lamin A should be produced. The lack of pre-lamin A would confirm the LMNALAO mutation is functioning as previously described in the literature. Once the generation of the novel transgenic mice is confirmed, data can begin to be collected.

The phenotypic consequences of the Zmpste24 knockout and LMNA(LAO/LAO) mouse will be studied and compared to both controls. A classic observation of HGPS is nuclear blebbing, which can be observed through immunofluorescence microscopy. Fluorescent lamin A antibodies can be utilized to view the nuclear envelope because it is composed partially of lamin A. Thus, if lamin A accumulates on the nuclear envelope, it can be observed. Novel transgenic mice are expected to have normal nuclear architecture, and lack lamin A accumulation since the direct synthesis of lamin A should prevent lamin A from building up on the nuclear envelope. The cells should appear similar to the wild-type mice. The Zmpste24 knockout mice should exhibit nuclear blebbing and lamin A accumulation, as described in previous research(Loren G. Fong et al., 2004). The percentage of cells exhibiting nuclear blebbing can be compared through statistical analysis. If the double mutant exhibits abnormal nuclear architecture or lamin A accumulation, it possibly suggests that Zmpste24 serves multiple functions in the cell and the disruption of this biochemical pathway would also cause HGPS like symptoms. In addition to microscopy, it is crucial to study the phenotypes at the organismal level as well.

Studying the phenotype at the organismal level is crucial to understanding the cascade effect caused by a mutation. Life expectancy, body weight, adipose tissues level, and bone density will all be studied. The wild-type mice and the double mutant mice should be normal in all of these categories. The double mutant mice should be phenotypically normal, since the nuclear architecture should be normal and LMNA(LAO/LAO) mice are phenotypically normal as well (Coffinier et al., 2010). Based upon previous research, the Zmpste24 knockout should have abnormally low levels of adipose tissue, body weight, and bone density (Loren G. Fong et al., 2004). Additionally, the Zmpste24 knockout mice should have lower life expectancies. If the double mutant mice are phenotypically normal, we will be able to conclude that Zmpste24 is only crucial for pre-lamin A cleavage at the carboxyl-terminal.

However, if the novel transgenic mice produce data that is similar to the Zmpste24 knockouts, then there is most likely an additional function of Zmpste24 that is disrupted once its primary sequence is altered. Also, this could potentially mean that there are multiple factors contributing to the HGPS phenotype.


Hutchinson-Gilford Progeria Syndrome is a devastating genetic condition caused by a silent mutation in exon eleven of the LMNA genet that leads to a deleterious protein called a progerin to be produced. At the molecular level, progerin accumulation causes “nuclear blebbing”. Afflicted individuals appear to prematurely age and ultimately succumb to cardiovascular disease. This experiment could provide valuable insight into the molecular mechanism that governs lamin A synthesis and potential alternate functions of Zmpste24, an enzyme that is crucial to processing pre-lamin A. A deeper understanding of this enzyme will help researchers determine which pathway should be utilized to generate treatments. Although this experiment does not produce a cure for HGPS, hopefully the information it could provide will be useful in bettering the lives of individuals

afflicted with this terminal condition.

Note: Eukaryon is published by students at Lake Forest College, who are solely responsible for its content. The views expressed in Eukaryon do not necessarily reflect those of the College. Articles published within Eukaryon should not be cited in bibliographies. Material contained herein should be treated as personal communication and should be cited as such only with the consent of the author.


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Eukaryon is published by students at Lake Forest College, who are solely responsible for its content. The views expressed in Eukaryon do not necessarily reflect those of the College.

Articles published within Eukaryon should not be cited in bibliographies. Material contained herein should be treated as personal communication and should be cited as such only with the consent of the author.