RIBOZYMES__________________________________________
The structural molecular biology of ribozymes took another great leap forward during the past two years. Before ribozymes were discovered in the early 1980s, all enzymes were thought to be proteins. No detailed structural information on ribozymes became available until 1994. Now, within the past two years, near atomic resolution crystal structures are available for almost all of the known ribozymes. The latest additions include ribonuclease P, group I intron structures, the ribosome (the peptidyl transferase appears to be a ribozyme) and several smaller ribozymes, including a Diels–Alderase, the glmS ribozyme and a new hammerhead ribozyme structure that reconciles 12 years of discord. Although not all ribozymes are metalloenzymes, acid-base catalysis appears to be a universal property shared by all ribozymes as well as many of their protein cousins
Introduction
Ribozymes are enzymes whose catalytic centers are composed entirely of RNA and therefore do not require proteins for catalysis (although many exist naturally as RNA–protein complexes).
All ribozymes were believed originally to be metalloenzymes, requiringMg2+ or other divalentmetal ions for both folding and catalysis. A ‘two-metal mechanism’ had been proposed in which hydratedMg2+ ions played the roles of general acids and bases. This prediction appears to have been correct for the group I intron. Acid-base catalysis appears to be a catalytic strategy so fundamental that it occurs in both protein and RNA enzymes; in many cases, it seems that the RNA itself, rather than acting as a passive scaffold for metal ion binding, is an active participant in acid-base catalysis in the sense that nucleotide functional groups, rather than metal complexes, often mimic the roles that amino acids play in the active sites of protein enzymes. Several of the small self-cleaving RNAs as a consequence do not strictly require divalent metal ions for catalysis and no divalent metal ions have yet been observed in the
active site of the peptidyltransferase, the ribozyme that is embedded in the ribosome.
Ribonuclease P
Ribonuclease P (RNase P) was the first true RNA enzyme identified. An RNA–protein complex, the catalytic subunit of bacterial RNase P is composed entirely of RNA (and it is thought that this is the case with the eukaryotic version as well). It processes precursor tRNAs and other RNAs required for cellular metabolism.
Group I intron
The folds of the various group I introns are quite similar, permitting comparisons between molecular species. The first Azoarcus structure was in a pre-catalytic state, in which both exons (the substrate of the reaction in which adjacent exons are spliced as the intron excises itself) were present. The Tetrahymena group I intron structure represents a state in which the 30 -terminal v-guanosine and a metal ion are present in the active site. The newer structures complement these two states with an enzyme– product complex, and a complex in which all substrate, ribozyme functional groups and predicted metal ions are present in the active site.
A Diels–Alderase ribozyme
The protein Diels–Alderase is a catalytic antibody whose structure is known. The structure of a Diels–Alder ribozyme is in both the unbound and enzyme–product complex states, revealing that the ribozyme uses a combination of proximity, spatial complementarity and electronic effects to activate stereoselective catalysis, reminiscent of the protein Diels–Alderase.
The glmS ribozyme
The glmS ribozyme is a recently discovered ribozyme that is unique in the world of naturally occurring ribozymes in two respects. First, it is a ribozyme that is also a riboswitch. Second, the regulatory effector of the ribozyme, glucosamine-6-phosphate (GlcN6P), is actually a functional group that binds to the ribozyme active site and participates in the acid-base catalysis of RNA self-cleavage. The glmS ribozyme is derived from a self-cleaving RNA sequence found in the 50 -untranslatedregion (50 - UTR) of the glmS message; it cleaves itself, inactivating the message, when the cofactor GlcN6P binds. GlcN6P production is thus regulated in many Gram-positive bacteria via this ribozyme-mediated negative-feedback mechanism.
The hammerhead ribozyme
Because it is small and has a simple cleavage mechanism, the hammerhead ribozyme is perhaps the best experimentally characterized RNA enzyme, and therefore, is a clear candidate for
Structural studies. The hammerhead motif consists of three base-paired stems flanking a central core of 15 conserved nucleotides. The conserved central bases are essential for ribozyme activity. Most of these conserved bases cannot form conventional Watson-Crick base pairs, but instead form more complex structures, which mediate RNA folding and catalysis. Substitution of any of the conserved bases with other naturally occurring bases, or sometimes even artificial alteration of their functional groups, results in diminished catalytic activity. In addition, two sets of base pairs in stem III and one pair in stem II are conserved; changing these to other base pairs either impairs or abolishes catalytic function.
Wednesday, July 27, 2011
my project on GENE THERAPY
GENE THERAPY_________________________________________
GENE THERAPY
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease.
Gene therapy is an experimental technique that uses genes to treat or prevent disease. In the future, this technique may allow doctors to treat a disorder by inserting a gene into a patient’s cells instead of using drugs or surgery.
It is a technique for correcting defective genes that are responsible for disease development. The most common form of gene therapy involves the insertion of functional genes into an unspecified genomic location in order to replace a mutatedgene, but other forms involve directly correcting the mutation or modifying normal gene that enables a viral infection. Although the technology is still in its infancy, it has been used with some success.
APPROACHES OF GENE THERAPY
• Replacing a mutated gene that causes disease with a healthy copy of the gene.
• Inactivating, or “knocking out,” a mutated gene that is functioning improperly.
• Introducing a new gene into the body to help fight a disease.
TYPES OF GENE THERAPY_______________________________
Gene therapy may be classified into the two following types:
Germ line gene therapy
In the case of germ line gene therapy, germ cells, i.e., sperm or eggs are modified by the introduction of functional genes, which are integrated into their genomes. Therefore, the change due to therapy would be heritable and would be passed on to later generations. This new approach, theoretically, should be highly effective in counteracting genetic disorders and hereditary diseases. However, many jurisdictions prohibit this for application in human beings, at least for the present, for a variety of technical and ethical reasons.
Somatic gene therapy
In the case of somatic gene therapy, the therapeutic genes are transferred into the somatic cells of a patient. Any modifications and effects will be restricted to the individual patient only, and will not be inherited by the patient's offspring or later generations.
Somatic cells are non-reproductive. Somatic cell therapy is viewed as a more conservative, safer approach because it affects only the targeted cells in the patient, and is not passed on to future generations. In other words, the therapeutic effect ends with the individual who receives the therapy. This type of therapy presents unique problems of its own. Often the effects of somatic cell therapy are short-lived. Because the cells of most tissues ultimately die and are replaced by new cells, repeated treatments over the course of the individual's life span are required to maintain the therapeutic effect. Transporting the gene to the target cells or tissue is also problematic.
Regardless of these difficulties, however, somatic cell gene therapy is appropriate and acceptable for many disorders, including cystic fibrosis, muscular dystrophy, cancer, and certain infectious diseases. Clinicians can even perform this therapy in utero, potentially correcting or treating a life-threatening disorder that may significantly impair a baby's health or development if not treated before birth.
CATEGORIES OF SOMATIC GENE THERAPY________________________
Somatic gene therapy can be broadly split into two categories:
EX VIVO TECHNIQUE
Ex vivo, which means exterior (where cells are modified outside the body and then transplanted back in again). In some gene therapy clinical trials, cells from the patient’s blood or bone marrow are removed and grown in the laboratory. The cells are exposed to the virus that is carrying the desired gene. The virus enters the cells and inserts the desired gene into the cells’ DNA. The cells grow in the laboratory and are then returned to the patient by injection into a vein. This type of gene therapy is called ex vivo because the cells are treated outside the body.
IN VIVO TECHNIQUE
In vivo, which means interior (where genes are changed in cells still in the body). This form of gene therapy is called in vivo, because the gene is transferred to cells inside the patient’s body.
Uses of gene therapy
Gene therapy is being used in many ways. For example, to:
• Replace missing or defective genes;
• Deliver genes that speed the destruction of cancer cells;
• Supply genes that cause cancer cells to revert back to normal cells;
• Deliver bacterial or viral genes as a form of vaccination;
• Provide genes that promote or impede the growth of new tissue; and;
• Deliver genes that stimulate the healing of damaged tissue.
A large variety of genes are now being tested for use in gene therapy.
Examples : a gene for the treatment of cystic fibrosis (a gene called CFTR that regulates chloride); genes for factors VIII and IX, deficiency of which is responsible for classic hemophilia (hemophilia A) and another form of hemophilia (hemophilia B), respectively; genes called E1A and P53 that cause cancer cells to undergo cell death or revert to normal; AC6 gene which increases the ability of the heart to contract and may help in heart failure; and VEGF, a gene that induces the growth of new blood vessels (angiogenesis) of use in blood vessel disease.
A short synthetic piece of DNA (called an oligonucleotide) is being used by researchers to "pre-treat" veins used as grafts for heart bypass surgery. The piece of DNA seems to switch off certain genes in the grafted veins to prevent their cells from dividing and thereby prevent atherosclerosis.
Delivery of genes into cells
Genes can be carried into cells by viruses. Viral vectors or carriers take advantage of the natural ability of a virus to enter a cell and deliver genetic material to the nucleus of the cell that contains its DNA. In developing virus carriers, the DNA coding for some or all of the normal genes of the virus to be used as a carrier are removed and replaced with a treatment gene. Most of these virus carriers are engineered so that they are able to enter cells, but they cannot reproduce themselves and so are innocuous.
Genes can also be delivered within tiny synthetic "envelopes" of fat molecules. Cell membranes contain a very high concentration of fat molecules. The fat molecule "envelope" can carry the therapeutic gene into the cell by being admitted through the cell membrane as if it were one of its own molecules.
Genes can also gain entrance into cells when an electrical charge is applied to the cell to create tiny openings in the membrane that surrounds a cell. This technique is called electroporation.
Route of administration of gene therapy
The choice of route for gene therapy depends on the tissue to be treated and the mechanism by which the therapeutic gene exerts its effect. Gene therapy for cystic fibrosis, a disease which effects cells within the lung and airway, may be inhaled. Most genes designed to treat cancer are injected directly into the tumor. Proteins such as factor VIII or IX for hemophilia are also being introduced directly into target tissue (the liver).
PROBLEMS OF GENE THERAPY____________________________
Some of the problems of gene therapy include:
• Short-lived nature of gene therapy – Before gene therapy can become a permanent cure for any condition, the therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be long-lived and stable. Problems with integrating therapeutic DNA into the genome and the rapidly dividing nature of many cells prevent gene therapy from achieving any long-term benefits. Patients will have to undergo multiple rounds of gene therapy.
• Immune response – Anytime a foreign object is introduced into human tissues, the immune system has evolved to attack the invader. The risk of stimulating the immune system in a way that reduces gene therapy effectiveness is always a possibility. Furthermore, the immune system's enhanced response to invaders that it has seen before makes it difficult for gene therapy to be repeated in patients.
• Problems with viral vectors – Viruses, the carrier of choice in most gene therapy studies, present a variety of potential problems to the patient —toxicity, immune and inflammatory responses, and gene control and targeting issues. In addition, there is always the fear that the viral vector, once inside the patient, may recover its ability to cause disease.
• Multigene disorders – Conditions or disorders that arise from mutations in a single gene are the best candidates for gene therapy. Unfortunately, some of the most commonly occurring disorders, such as heart disease, high blood pressure, Alzheimer's disease, arthritis, and diabetes, are caused by the combined effects of variations in many genes. Multigene or multifactorial disorders such as these would be especially difficult to treat effectively using gene therapy.
• Chance of inducing a tumor (insertional mutagenesis) - If the DNA is integrated in the wrong place in the genome, for example in a tumor suppressor gene, it could induce a tumor. This has occurred in clinical trials for X-linked severe combined immunodeficiency (X-SCID) patients, in which hematopoietic stem cells were transduced with a corrective transgene using a retrovirus, and this led to the development of T cell leukemia in 3 of 20 patients.
APPLICATIONS OF GENE THERAPY________________________
A "bionic chip"
A new "bionic chip" has been developed to help gene therapists using electroporation to slip fragments of DNA into cells. Electroporation was originally a hit-or-miss technique because there was no way to determine how much of an electrical jolt it took to open the cell membrane.
The "bionic chip" solves this problem. It contains a single living cell embedded in a tiny silicon circuit. The cell acts as a diode, or electrical gate. When it is hit with just the right charge, the cell membrane opens, allowing the electricity to pass from the top to the bottom of the bionic chip. By recording what voltage caused this phenomenon to occur, it is now posssible to determine precisely how much electricity it takes to pry open different types of cells.
GENE THERAPY IN FUTURE______________________________
The potential of gene therapy is great but, compared to its promise, the results to date are still quite limited. However, the benefits of gene therapy are believed to be on the near horizon. Gene therapy is one of the hottest areas of medical research today.
The remarkable advances in genetics, including the human genome project, have opened new doors for the exploration of gene therapy. New technologies are needed to speed the progress of gene therapy. As these new technologies such as the "bionic chip" arrive, we believe that, without a doubt, gene therapy will play an increasingly important and prominent part in medicine in the decades to come.
GENE THERAPY
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease.
Gene therapy is an experimental technique that uses genes to treat or prevent disease. In the future, this technique may allow doctors to treat a disorder by inserting a gene into a patient’s cells instead of using drugs or surgery.
It is a technique for correcting defective genes that are responsible for disease development. The most common form of gene therapy involves the insertion of functional genes into an unspecified genomic location in order to replace a mutatedgene, but other forms involve directly correcting the mutation or modifying normal gene that enables a viral infection. Although the technology is still in its infancy, it has been used with some success.
APPROACHES OF GENE THERAPY
• Replacing a mutated gene that causes disease with a healthy copy of the gene.
• Inactivating, or “knocking out,” a mutated gene that is functioning improperly.
• Introducing a new gene into the body to help fight a disease.
TYPES OF GENE THERAPY_______________________________
Gene therapy may be classified into the two following types:
Germ line gene therapy
In the case of germ line gene therapy, germ cells, i.e., sperm or eggs are modified by the introduction of functional genes, which are integrated into their genomes. Therefore, the change due to therapy would be heritable and would be passed on to later generations. This new approach, theoretically, should be highly effective in counteracting genetic disorders and hereditary diseases. However, many jurisdictions prohibit this for application in human beings, at least for the present, for a variety of technical and ethical reasons.
Somatic gene therapy
In the case of somatic gene therapy, the therapeutic genes are transferred into the somatic cells of a patient. Any modifications and effects will be restricted to the individual patient only, and will not be inherited by the patient's offspring or later generations.
Somatic cells are non-reproductive. Somatic cell therapy is viewed as a more conservative, safer approach because it affects only the targeted cells in the patient, and is not passed on to future generations. In other words, the therapeutic effect ends with the individual who receives the therapy. This type of therapy presents unique problems of its own. Often the effects of somatic cell therapy are short-lived. Because the cells of most tissues ultimately die and are replaced by new cells, repeated treatments over the course of the individual's life span are required to maintain the therapeutic effect. Transporting the gene to the target cells or tissue is also problematic.
Regardless of these difficulties, however, somatic cell gene therapy is appropriate and acceptable for many disorders, including cystic fibrosis, muscular dystrophy, cancer, and certain infectious diseases. Clinicians can even perform this therapy in utero, potentially correcting or treating a life-threatening disorder that may significantly impair a baby's health or development if not treated before birth.
CATEGORIES OF SOMATIC GENE THERAPY________________________
Somatic gene therapy can be broadly split into two categories:
EX VIVO TECHNIQUE
Ex vivo, which means exterior (where cells are modified outside the body and then transplanted back in again). In some gene therapy clinical trials, cells from the patient’s blood or bone marrow are removed and grown in the laboratory. The cells are exposed to the virus that is carrying the desired gene. The virus enters the cells and inserts the desired gene into the cells’ DNA. The cells grow in the laboratory and are then returned to the patient by injection into a vein. This type of gene therapy is called ex vivo because the cells are treated outside the body.
IN VIVO TECHNIQUE
In vivo, which means interior (where genes are changed in cells still in the body). This form of gene therapy is called in vivo, because the gene is transferred to cells inside the patient’s body.
Uses of gene therapy
Gene therapy is being used in many ways. For example, to:
• Replace missing or defective genes;
• Deliver genes that speed the destruction of cancer cells;
• Supply genes that cause cancer cells to revert back to normal cells;
• Deliver bacterial or viral genes as a form of vaccination;
• Provide genes that promote or impede the growth of new tissue; and;
• Deliver genes that stimulate the healing of damaged tissue.
A large variety of genes are now being tested for use in gene therapy.
Examples : a gene for the treatment of cystic fibrosis (a gene called CFTR that regulates chloride); genes for factors VIII and IX, deficiency of which is responsible for classic hemophilia (hemophilia A) and another form of hemophilia (hemophilia B), respectively; genes called E1A and P53 that cause cancer cells to undergo cell death or revert to normal; AC6 gene which increases the ability of the heart to contract and may help in heart failure; and VEGF, a gene that induces the growth of new blood vessels (angiogenesis) of use in blood vessel disease.
A short synthetic piece of DNA (called an oligonucleotide) is being used by researchers to "pre-treat" veins used as grafts for heart bypass surgery. The piece of DNA seems to switch off certain genes in the grafted veins to prevent their cells from dividing and thereby prevent atherosclerosis.
Delivery of genes into cells
Genes can be carried into cells by viruses. Viral vectors or carriers take advantage of the natural ability of a virus to enter a cell and deliver genetic material to the nucleus of the cell that contains its DNA. In developing virus carriers, the DNA coding for some or all of the normal genes of the virus to be used as a carrier are removed and replaced with a treatment gene. Most of these virus carriers are engineered so that they are able to enter cells, but they cannot reproduce themselves and so are innocuous.
Genes can also be delivered within tiny synthetic "envelopes" of fat molecules. Cell membranes contain a very high concentration of fat molecules. The fat molecule "envelope" can carry the therapeutic gene into the cell by being admitted through the cell membrane as if it were one of its own molecules.
Genes can also gain entrance into cells when an electrical charge is applied to the cell to create tiny openings in the membrane that surrounds a cell. This technique is called electroporation.
Route of administration of gene therapy
The choice of route for gene therapy depends on the tissue to be treated and the mechanism by which the therapeutic gene exerts its effect. Gene therapy for cystic fibrosis, a disease which effects cells within the lung and airway, may be inhaled. Most genes designed to treat cancer are injected directly into the tumor. Proteins such as factor VIII or IX for hemophilia are also being introduced directly into target tissue (the liver).
PROBLEMS OF GENE THERAPY____________________________
Some of the problems of gene therapy include:
• Short-lived nature of gene therapy – Before gene therapy can become a permanent cure for any condition, the therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be long-lived and stable. Problems with integrating therapeutic DNA into the genome and the rapidly dividing nature of many cells prevent gene therapy from achieving any long-term benefits. Patients will have to undergo multiple rounds of gene therapy.
• Immune response – Anytime a foreign object is introduced into human tissues, the immune system has evolved to attack the invader. The risk of stimulating the immune system in a way that reduces gene therapy effectiveness is always a possibility. Furthermore, the immune system's enhanced response to invaders that it has seen before makes it difficult for gene therapy to be repeated in patients.
• Problems with viral vectors – Viruses, the carrier of choice in most gene therapy studies, present a variety of potential problems to the patient —toxicity, immune and inflammatory responses, and gene control and targeting issues. In addition, there is always the fear that the viral vector, once inside the patient, may recover its ability to cause disease.
• Multigene disorders – Conditions or disorders that arise from mutations in a single gene are the best candidates for gene therapy. Unfortunately, some of the most commonly occurring disorders, such as heart disease, high blood pressure, Alzheimer's disease, arthritis, and diabetes, are caused by the combined effects of variations in many genes. Multigene or multifactorial disorders such as these would be especially difficult to treat effectively using gene therapy.
• Chance of inducing a tumor (insertional mutagenesis) - If the DNA is integrated in the wrong place in the genome, for example in a tumor suppressor gene, it could induce a tumor. This has occurred in clinical trials for X-linked severe combined immunodeficiency (X-SCID) patients, in which hematopoietic stem cells were transduced with a corrective transgene using a retrovirus, and this led to the development of T cell leukemia in 3 of 20 patients.
APPLICATIONS OF GENE THERAPY________________________
A "bionic chip"
A new "bionic chip" has been developed to help gene therapists using electroporation to slip fragments of DNA into cells. Electroporation was originally a hit-or-miss technique because there was no way to determine how much of an electrical jolt it took to open the cell membrane.
The "bionic chip" solves this problem. It contains a single living cell embedded in a tiny silicon circuit. The cell acts as a diode, or electrical gate. When it is hit with just the right charge, the cell membrane opens, allowing the electricity to pass from the top to the bottom of the bionic chip. By recording what voltage caused this phenomenon to occur, it is now posssible to determine precisely how much electricity it takes to pry open different types of cells.
GENE THERAPY IN FUTURE______________________________
The potential of gene therapy is great but, compared to its promise, the results to date are still quite limited. However, the benefits of gene therapy are believed to be on the near horizon. Gene therapy is one of the hottest areas of medical research today.
The remarkable advances in genetics, including the human genome project, have opened new doors for the exploration of gene therapy. New technologies are needed to speed the progress of gene therapy. As these new technologies such as the "bionic chip" arrive, we believe that, without a doubt, gene therapy will play an increasingly important and prominent part in medicine in the decades to come.
Saturday, July 23, 2011
Developmental genetics
GO TO THIS LINK PLZ
http://www.slideshare.net/xulkifal/developmental-genetics-4294650
www.slideshare.net/xulkifal/developmental-genetics-4294650
http://www.slideshare.net/xulkifal/developmental-genetics-4294650
www.slideshare.net/xulkifal/developmental-genetics-4294650
Saturday, July 3, 2010
Genes anticipation
In genetics, anticipation is a phenomenon whereby the symptoms of a genetic disorder become apparent at an earlier age as it is passed on to the next generation. In most cases, an increase of severity of symptoms is also noted. Anticipation is common in trinucleotide repeat disorders such as Huntington's disease and myotonic dystrophy where a dynamic mutation in DNA occurs. All of these diseases have neurological symptoms. Prior to the understanding of the genetic mechanism for anticipation, it was debated whether anticipation was a true biological phenomenon or whether the earlier age of diagnosis was related to heightened awareness of disease symptoms within a family.
Trinucleotide Repeats and Expansion
Trinucleotide repeats are apparent in a number of loci in the human genome. They have been found in introns, exons and 5' or 3' UTR's. They consist of a pattern of three nucleotides (e.g. CGG) which is repeated a number of times. During meiosis, unstable repeats can undergo triplet expansion (see later section); in this case, the germ cells produced have a greater number of repeats than are found in the somatic tissues.The mechanism behind the expansion of the triplet repeats is not well understood. One hypothesis is that the increasing number of repeats influence the overall shape of the DNA, which can have an effect on its interaction with DNA polymerase and thus the expression of the gene.
Disease mechanisms
For many of the loci, trinucleotide expansion is harmless, but in some areas expansion has detrimental effects that cause symptoms. When the trinucleotide repeat is present within the protein-coding region, the repeat expansion leads to production of a mutant protein with gain of function. This is the case for Huntington's disease, where the trinucleotide repeat encodes a long stretch of glutamine residues. When the repeat is present in an untranslated region, it could affect the expression of the gene in which the repeat is found (ex. fragile X) or many genes through a dominant negative effect (ex. myotonic dystrophy).
In order to have a deleterious effect, the number of repeats must cross a certain threshold. For example, normal individuals have between 5 and 30 CTG repeats within the 3' UTR of DMPK, the gene that is altered in myotonic dystrophy. If the number of repeats becomes greater than 50, the person is only mildly affected - perhaps having only cataracts. However, meiotic instability could result in a dynamic mutation that increases the number of repeats in offspring inheriting the mutant allele. Once the number of copies reaches over 100, the disease will manifest earlier in life (although the individual will still reach adulthood before the symptoms are evident) and the symptoms will be more severe - including electrical myotonia. As the number progresses upwards past 400, the symptoms show themselves during childhood or infancy.
Examples of Diseases showing Anticipation
Some examples of diseases showing anticipation, and some of the corresponding repeat sequences.Spinocerebellar ataxia
Spinocerebellar ataxia (SCA) is a progressive, degenerative, genetic disease with multiple types, each of which could be considered a disease in its own right. The first ataxia gene was identified in 1993 for a dominantly inherited type. It was called “Spinocerebellar ataxia type 1" (SCA1). Subsequently, as additional dominant genes were found they were called SCA2, SCA3, etc. Usually, the "type" number of "SCA" refers to the order in which the gene was found. At this time, there are at least 29 different gene mutations which have been found (not all listed).Many SCAs below fall under the category of polyglutamine diseases, which are caused when a disease-associated protein (i.e. ataxin-1, ataxin-3, etc.) contains a glutamine repeat beyond a certain threshold. In most dominant polyglutamine diseases, the glutamine repeat threshold is approximately 35, except for SCA3 which is beyond 50. Polyglutamine diseases are also known as "CAG Triplet Repeat Disorders" because CAG is the codon which codes for the amino acid glutamine. Many prefer to refer to these also as polyQ diseases since "Q" is the one-letter reference for glutamine.
Signs and symptoms
Spinocerebellar ataxia (SCA) is one of a group of genetic disorders characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs, and different ataxias are known to affect different regions within the cerebellum.As with other forms of ataxia, SCA results in unsteady and clumsy motion of the body due to a failure of the fine coordination of muscle movements, along with other symptoms.
The symptoms of an ataxia vary with the specific type and with the individual patient. Generally, a person with ataxia retains full mental capacity but may progressively lose physical control.
Genetics: A conceptual Approach & Problem Solving CD-ROM
CAUSES
The hereditary ataxias are categorized by mode of inheritance and causative gene or chromosomal locus. The hereditary ataxias can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner.
- Many types of autosomal dominant cerebellar ataxias are now known for which specific genetic information is available. Synonyms for autosomal dominant cerebellar ataxias (ADCA) used prior to the current understanding of the molecular genetics were Marie's ataxia, inherited olivopontocerebellar atrophy, cerebello-olivary atrophy, or the more generic term "spinocerebellar degeneration." (Spinocerebellar degeneration is a rare inherited neurological disorder of the central nervous system characterized by the slow degeneration of certain areas of the brain. There are three forms of spinocerebellar degeneration: Types 1, 2, 3. Symptoms begin during adulthood.)
- There are five typical autosomal recessive disorders in which ataxia is a prominent feature: Friedreich ataxia, ataxia-telangiectasia, ataxia with vitamin E deficiency, ataxia with oculomotor apraxia (AOA), spastic ataxia. Disorder Subdivisions: Friedreich's ataxia, Spinocerebellar ataxia, Ataxia telangiectasia, Vasomotor ataxia, Vestibulocerebellar, Ataxiadynamia, Ataxiophemia, Olivopontocerebellar atrophy, and Charcot-Marie-Tooth disease.
- There have been reported cases where a polyglutamine expansion may lengthen when passed down, which often can result in an earlier age-of-onset and a more severe disease phenotype for individuals who inherit the disease allele. This falls under the category of genetic anticipation.
Treatment
There is no known cure for spinocerebellar ataxia, which is a progressive disease (it gets worse with time), although not all types cause equally severe disability.Treatments are generally limited to softening symptoms, not the disease itself. The condition is considered to be irreversible. A person with this disease will usually end up needing to use a wheelchair, and eventually they may need assistance to perform daily tasks.
The treatment of incoordination or ataxia, then mostly involves the use of adaptive devices to allow the ataxic individual to maintain as much independence as possible. Such devices may include a cane, crutches, walker, or wheelchair for those with impaired gait; devices to assist with writing, feeding, and self care if hand and arm coordination are impaired; and communication devices for those with impaired speech.
Many patients with hereditary or idiopathic forms of ataxia have other symptoms in addition to ataxia. Medications or other therapies might be appropriate for some of these symptoms, which could include tremor, stiffness, depression, spasticity, and sleep disorders, among others.
Both onset of initial symptoms and duration of disease can be subject to variation. If the disease is caused by a polyglutamine trinucleotide repeat CAG expansion, a longer expansion may lead to an earlier onset and a more radical progression of clinical symptoms.
Thursday, July 1, 2010
CLONING
http://www.slideshare.net/xulkifal/cloningpresentation of cloning
- watch video
- http://www.youtube.com/user/zulkifalyousaf#p/a/u/0/df287vPbrUs
- ZULKIFAL YOUSAF [email_address]
- Cloning
- “ Cloning” in biology is the process of similar producing populations of genetically identical individuals that occurs in nature when organisms such as bacteria, insects or plants reproduce asexually.
- Types Of Cloning
- Reproductive cloning
- Therapeutic cloning
- Recombinant DNA cloning
- Reproductive Cloning
- Reproductive cloning is a type of cloning which is performed for the purpose of creating a duplicate copy of another organism.
- In somatic cell nuclear transfer, scientists extract the nucleus of a somatic cell, a cell which can come from anywhere in the body, and insert it into an egg which has had its nucleus removed.
- Continued…
- The egg is stimulated, and it begins dividing and growing, developing into an embryo which can be implanted into a gestational surrogate and carried to term.
- It is also possible to manipulate the genetic material used in reproductive cloning using recombinant DNA technology to alter DNA.
- Therapeutic Cloning
- Therapeutic cloning is cloning which is performed for the purpose of medical treatment. For example, it could theoretically be used to grow a replacement organ, to generate skin for a burn victim, or to create nerve cells for someone suffering from brain damage or a neurological condition.
- Formally, this type of cloning is called somatic cell nuclear transfer. It involves extracting the nucleus of a cell, and putting the nucleus into an egg which has been de-nucleated. Then, the egg is allowed to divide and grow. In therapeutic cloning, the growing egg is used as a source of stem cells, which are undifferentiated cells which can grow into a wide variety of different types of cells.
- RECOMBINANT DNA CLONING
- The fragment of DNA to be amplified is first inserted into a cloning vector.
- MOST COMMONLY USED VECTOR:-
- The most popular vectors currently in use consist of either small circular DNA molecules (plasmids) or bacterial viruses (phage).
- The vectors contain genetic information that allows bacterial DNA replication machinery to copy them.
- After insertion of the foreign DNA, the plasmid or phage vector is re-introduced into a bacterial cell.
- The growing bacterial culture replicates the foreign DNA, along with the vector, in hundreds of copies per cell.
- CONTINUE…
- This process yields multiple, identical clones of the original recombinant molecule.
- USES OF RECOMBINANT DNA CLONING
- Recombinant DNA cloning is used to produce genetic material in large enough quantities for scientific use. There are a variety of uses for this reproduced, or cloned, genetic material.
- Microbial Cells
- Isolation of Proteins
- Identification of Mutations
- Diagnosis of Hereditary Diseases
- Transferring Genes Between Organisms
- Ethical Issues Of Cloning
- Cloning has become a contentious ethical and scientific issue in some parts of the world.
- Some people believe that life begins at conception, and they feel that reproductive cloning is unnatural and that it could potentially violate their religious beliefs.
- Several nations have passed resolutions to explicitly ban human cloning, out of concern about ethical issues.
- Advantages Of Cloning
- Medical treatment is that it would allow doctors to grow replacements for missing and damaged body parts for their patients. This would eliminate organ and tissue shortages
- Using cloned body parts would also eliminate the need for immunosuppressive drugs, and reduce the risk of rejection and other problems which are commonly associated with transplants.
- Cloning research on mice has suggested that new nerve cells can be grown with reproductive cloning techniques and used to repair damaged brains, an application which could be useful for people with dementia, Alzheimer's disease, or strokes.Investigative Reports: The Human Cloning Race [VHS]
- Cloning research on mice has suggested that new nerve cells can be grown with reproductive cloning techniques and used to repair damaged brains, an application which could be useful for people with dementia, Alzheimer's disease, or strokes.Investigative Reports: The Human Cloning Race [VHS]
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