Insight study of Hutchinson Gilford Progeria Syndrome

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Hutchinson-Gilford progeria syndrome is an extremely rare disorder characterized by premature aging of postnatal onset. The main clinical and radiological features include alopecia, thin skin, hypoplasia of nails, loss of subcutaneous fat, stiffness of joints and osteolysis. Intelligence is not impaired. Early death is caused by atherosclerosis or cerebrovascular disease, and failure to thrive. Most cases are sporadic, caused by a de novo dominant recurrent truncating mutation within the lamin A gene. Numerous progeroid syndromes represent differential diagnoses for this entity.

1 introduction

Aging is an extremely complicated process and is known to be driven by a variety of different mutually interacting mechanisms. Conventionally, it is seen as a process of progressive failure of homeostasis involving genes for maintenance and repair, environmental factors leading to molecular damage and molecular heterogeneity, and chance events with potentially significant consequences for death (Alberts et al 2002). Since several human progeroid syndromes (PSs) (human premature aging-like syndromes) are characterized by features resembling precocious aging, the identification of the genes involved in PSs has provided important clues to understanding the molecular mechanisms underlying normal human aging (Hutchinson 1886, Gilford 1904; Martin 1978, 1985). The word Progeria comes from the Greek progeros meaning 'prematurely old'. The Greek word pro means 'before', while the word geras means 'old age'. HGPS (Hutchinson-Gilford Progeria Syndrome) or Progeria is an extremely rare, fatal genetic condition. Progeria affects children and gives them an appearance of accelerated aging. The classic type of Progeria (there are different forms) is Hutchinson-Gilford Progeria Syndrome (HGPS). Progeria was first described in an academic journal by Dr. Jonathan Hutchinson in 1886, and Dr. Hastings Gilford in 1897 - both in England. According to Hayley's Page "At present there are 53 known cases of Progeria around the world and only 2 in the UK" (till 2008).( Hayley's Progeria Page is dedicated to Hayley Okines, who suffers from HGPS, or Progeria. A ten-year-old Progeria child will look like an eighty-year-old - but her mind is still that of a ten-year-old). There is a reported incidence of Progeria of approximately 1 in every 4 to 8 million newborns. Over the last 15 years the following countries have had reported cases -

Algeria, Argentina, Australia, Austria ,Canada, China, Cuba, England, France, Germany, Israel, Italy, India, Mexico, the Netherlands, Poland, Puerto Rico, South Africa, South America, South Korea, Switzerland, Turkey, the US, Venezuela, Vietnam and Yugoslavia. Hutchinson-Gilford progeria syndrome (HGPS) is characterized by clinical features that develop in childhood and resemble some features of accelerated aging. Children with progeria usually appear normal at birth and in early infancy. Early findings such as midfacial cyanosis, "Sculpted nose," and "Sclerema" (or "Sclerodermatous skin") may suggest HGPS at or shortly after birth. Profound failure to thrive occurs during the first year. Characteristic facies, partial alopecia progressing to total alopecia, loss of subcutaneous fat, stiffness of joints, bone changes, and abnormal tightness of the skin over the abdomen and upper thighs usually become apparent during the second to third year. Motor and mental development are normal. As a result of severe failure to thrive, affected individuals do not become sexually mature and do not reproduce. Individuals with progeria develop severe atherosclerosis, usually without obvious abnormalities in lipid profiles [Gordon et al 2005]. Death occurs as a result of complications of cardiac or cerebrovascular disease (heart attack or stroke) generally between age six and 20 years, with an average life span of approximately 13 years. One individual died of a chondrosarcoma of the chest wall at age 13 years [Oshima et al 1996]. Death due to cardiovascular abnormalities occurs in approximately 75% of Hutchinson-Gilford progeria syndrome (HGPS) patients. Other causes of death mentioned in the literature include stroke, marasmus , inanition, seizures, and accidental head trauma . Cataracts of the lens, tumors, and insulin resistance have been noted occasionally.


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. The condition results from new mutations in the LMNA gene, and almost always occurs in people with no history of the disorder in their family or mutations in the LMNA gene cause Hutchinson-Gilford progeria syndrome. Eriksson and colleagues (2003) identified the disease causing mutations in the LMNA gene (encoding lamin A/C). The official name of this gene is "lamin A/C." LMNA is the gene's official symbol. The LMNA gene is also known by other names as HGPS ,LMN1, LMNA_HUMAN ,LMNC . The LMNA gene provides instructions for making several slightly different proteins called lamins. The two major proteins produced from this gene, lamin A and lamin C, are made in most of the body's cells. These proteins have a nearly identical sequence of protein building blocks (amino acids). The small difference in the sequence makes lamin A longer than lamin C. Lamins A and C are structural proteins called intermediate filament proteins. Intermediate filaments provide stability and strength to cells. Lamins A and C are essential scaffolding (supporting) components of the nuclear envelope, which is a structure that surrounds the nucleus in cells. Specifically, these proteins are located in the nuclear lamina, a mesh-like layer of intermediate filaments that is attached to the inner membrane of the nuclear envelope. The nuclear envelope regulates the movement of molecules into and out of the nucleus, and researchers believe it may play a role in regulating the activity of certain genes. The lamin A protein must be processed within the cell before becoming part of the lamina. Its initial form, called prelamin A, undergoes a complex series of steps that are necessary for the protein to be inserted into the lamina. Lamin C does not have to undergo this processing before becoming part of the lamina. A specific mutation in the LMNA gene has been found in most patients with Hutchinson-Gilford progeria syndrome. This mutation changes a single DNA building block (nucleotide) in the gene. Specifically, the mutation replaces the nucleotide cytosine with the nucleotide thymine at position 1824 (written as C1824T). This mutation is also sometimes noted as Gly608Gly or G608G, which refers to the position in the lamin A protein affected by the mutation. The C1824T mutation leads to an abnormal version of the lamin A protein called progerin, which is missing 50 amino acids near one end. The location of this mutation does not affect the production of lamin C. Other mutations in the LMNA gene have been identified in a small number of people with the features of Hutchinson-Gilford progeria syndrome. The mutations responsible for this disorder result in an abnormal version of lamin A that cannot be processed correctly within the cell. When the altered protein is incorporated into the lamina, it can disrupt the shape of the nuclear envelope. Over time, a buildup of this altered protein appears to damage the structure and function of the nucleus, making cells more likely to die prematurely. Cytogenetic Location: The LMNA gene is located on the long (q) arm of chromosome 1 between positions 21.2 and 21.3. More precisely, the LMNA gene is located from base pair 154,351,121 to base pair 154,376,494 on chromosome 1.


Hutchinson-Gilford progeria syndrome (HGPS) is related to aberrant processing of the nuclear envelope protein lamin A and accumulation of farnesylated prelamin A .

Autosomal dominant mutations in the LMNA gene, located on band 1q21.1-1q21.3, are responsible for most cases of HGPS. De novo mutations associated with advanced paternal age are responsible for most cases, although maternal transmission of a mutant LMNA gene from an asymptomatic mother who manifested somatic and gonadal mosaicism has also been reported. In addition, autosomal recessive transmission has also been suggested to account for the reported development of HGPS in several sets of siblings born to unaffected parents. The LMNA genes encodes the nuclear A-type lamins, which are type V intermediate filament proteins that localize to the cell nucleus and form the nuclear lamina, a structure that supports the nuclear envelope. They are important in maintaining nuclear stability and organizing nuclear chromatin. The nuclear lamins may also play a role in regulating gene expression, DNA synthesis, and DNA repair.

The most common LMNA mutation involves a C-->T transition at nucleotide 1824 (G608G). This substitution results in the activation of a cryptic splice donor site in exon 11, which results in a 150-base pair deletion and a truncated lamin A protein, called progerin. The abnormal progerin protein acts in a dominant-negative manner to prevent the normal assembly of nuclear lamins into the nuclear lamina. After translation, the mutant preprogerin protein undergoes normal farnesylation of a CAAX tetrapeptide motif located at the carboxyterminus. The farnesylated preprogerin protein is then incorporated into the nuclear membrane. However, the mutant, truncated protein lacks an important posttranslational processing signal required for cleavage of the preprogerin protein at the carboxyterminus. This cleavage is required for the release of prelamin A from the nuclear membrane, thus allowing its incorporation into the nuclear lamina. The abnormal progerin protein forms insoluble cytoplasmic aggregates. As a result of the absence of lamin A in the nuclear lamina, the cell nuclei from HGPS patients display abnormal nuclear blebbing and aberrant nuclear shapes. Abnormal chromosome segregation and delayed onset and progression of mitosis have also been demonstrated.

1.2 Treatment & Medication of HGPS

The Progeria Research Foundation created a medicine based on fernesyltransferase inhibitors . Farnesyltransferase inhibitors, or FTIs, are a class of drugs that can reverse an abnormality in Progeria cells in the laboratory. The nucleus (plural nuclei) is the structure at the center of each cell that contains DNA. Unlike the round nuclei from normal cells, Progeria cells have abnormally shaped nuclei. These abnormally shaped nuclei with multiple "lobes" can even look like a cluster of grapes or bubbles. In the laboratory, treating Progeria cells with FTIs restored their nuclei to a normal appearance, as recently reported in five journal articles and reviewed in another . The finding that FTIs efficiently reverse this disease-related abnormal shape at the cellular level has provided compelling proof-of-principle that these drugs may be effective in improving disease in children with Progeria. Treating Cells in the Laboratory; FTI Improves Progeria in Cell Cultures: The gene LMNA normally produces

Fig.1 - FTI treated cell

a protein called prelamin A. When this gene mutates, it causes Progeria. Prelamin A has a molecule attached to the end of it called a farnesyl group. It needs this farnesyl molecule to anchor the protein to the nuclear rim. In normal cells, this farnesyl group is removed, but this step does not take place in Progeria and the progerin protein remains attached to the rim, where it appears the progerin does its damage. FTIs function by not allowing the farnesyl molecule to attach onto progerin in the first place, thus "neutralizing" the damaging properties of progerin and restoring the nucleus to a more normal state. Further optimism has come from recent studies with Progeria mice whose disease symptoms were prevented by FTI treatment recent studies with Progeria mice whose disease symptoms were prevented by FTI treatment . The protein that is responsible for Progeria is called progerin. In order to block normal cell function and cause Progeria, a molecule called a "farnesyl group" must be attached to the progerin protein. FTIs act by blocking (inhibiting) the attachment of the farnesyl group onto progerin. They believe that if the FTI drug can effectively block this farnesyl group attachment in children with Progeria, then progerin may be "paralyzed" and Progeria may be improved. Based on the current information on Hutchinson-Gilford progeria syndrome here we also performed the phylogenetic analysis of LMNA gene sequences of Anopheles gambiae , Danio rerio , Rattus norvegicus , Mus musculus , Bos Taurus , Canis familiaris , Pan troglodytes ,with the similar one of Homo sapiens.

2 Methods

Performed the phylogenetic analysis among the mRNA (nucleotide) sequences of HGPS causing gene LMNA. Firstly I find the sequences which are homologous to the sequence of LMNA gene of human from Homologene database of NCBI .Then download these sequences in FASTA format. These sequences are of

Pan troglodytes ; gi|114560152|ref|XM_513875.2|

Canis familiaris ; gi|73960919|ref|XM_859341.1|

Bos taurus ; gi|77404181|ref|NM_001034053.1|

Mus musculus ; gi|50355691|ref|NM_001002011.1|

Rattus norvegicus ; gi|50355946|ref|NM_001002016.1|

Danio rerio ; gi|23308640|ref|NM_152971.1|

Anopheles gambiae ; gi|158297174|ref|XM_317447.4|

Homo sapiens ; gi|153281093|ref|NM_170707.2|

After that I put these sequences into the CLUSTAL - X offline bioinformatics multiple sequence alignment tool and then studied those sequences under the phylip package . the output file is to be run in Tree view which shows following result :

Phylogram Tree shows evolutionary relationship among the organisms and the distance shows the closeness among them.

Boot strap value is 10.0 for all organisms defines that the all taken sequences are truly homologous and their genes are same as LMNA of human.

The calculated tree is unrooted shows that the origin of all these organism comes from a unknown source.

These phylogram tree and boot strap values related with these organisms may increase the area of experiment to discover the new methods to diminish the effect of mutation in LMNA gene .


Fig.2 Phylip tree


Fig 3- Boot strap value of tree


Progeria is a genetic disorder rarely encountered and is characterized by features of premature aging. It is also known as "Hutchinson-Gilford Progeria syndrome". In this syndrome, the rate of ageing is accelerated up to seven times that of normal. The average life span is 13 years (range 7- 27 years) occasional survival till the age of 45 years. The death is mainly due to cardiovascular complications like myocardial infarction or congestive heart failure. The probable cause is a mutation in the Lamin located in the nuclear matrix. Increase in the blood hyaluronic acid levels is responsible for sclerodermatous changes and cardiovascular abnormalities. In progeria, rise in blood and serum levels of low-density lipoprotein and cholesterol and total lipids is commonly seen. Failure to thrive may be seen possibly due to a bioinactive growth hormone and lack of vasculogenesis caused by excessive excretion of hyaluronic acid. The affected children are normal at birth and grow normally till about the end of the first year, when both normal growth and gain in weight slow down. Progeria Research Foundation started clinical trials of the FTI based medicine . They are usually given to people in pill form, twice per day. Parents of young children will be able to open the pill and mix the treatment with food. To date the only experience with the FTI proposed for the Progeria drug therapy trial is in a series of adults with a variety of tumors, and in children with terminal brain cancer. All of these patients had previously been treated with surgery, radiation therapy, and chemotherapy for their cancer. As such, it was difficult to know with certainty the cause of all side effects when experimental drugs were administered. The two most common side effects associated with the FTI in children taking the pills twice a day (as will be performed for children with Progeria) were diarrhea and changes in certain blood tests of liver function. The diarrhea was easily prevented by starting an anti-diarrhea medicine first, while the changes in the liver function tests never caused any problems and resolved. Like most drugs, there is also the possibility of rare or unknown side effects that have not yet been identified. For this reason, patients on this medicine will be followed very carefully and the dose of the medicine modified if any new or unexpected side effects arise. Nothing will give us 100% assurance of safety, but the prior work done with these drugs in mouse models and in people (both adults and children) without Progeria makes this a great candidate treatment. Clinical testing in cancer studies has shown us that these drugs can be used in adults and children with tolerable side effects as noted above. The known side effects will be explained in detail to each family as they consider entering the clinical trial. However, while unlikely, there may be potentially new side effects with FTI treatment in Progeria. This is why the decision to move into treatment is so difficult for everyone, especially children with Progeria and their families, who ultimately make highly personal treatment decisions for themselves. They plan to have a clinical trial up and running in the near future, and are working every day towards that goal. There are the three important things that Progeria families should do now in order to optimize the chance of being included in the clinical trial.