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Table of Contents > Genomics > Ligase chain reaction (LCR) Print

Ligase chain reaction (LCR)

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Also listed as: Ligase detection reaction (LDR)
Related terms
Background
Methods
Research
Implications
Limitations
Safety
Future research
Author information
Bibliography

Related Terms
  • Amplicon, annealing, autoradiography, CAD, CHD, congenital adrenal hyperplasia, coronary artery disease, coronary heart disease, cystic fibrosis, denaturation, DNA ligase, electrophoresis, fluorescent DNA sequencer, gap-ligase chain reaction (G-LCR), gonorrhea, herpes simplex virus, HIV, human immunodeficiency virus, hybridization, hyperkalemic periodic paralysis, Leber's hereditary optic neuropathy, ligase chain reaction (LCR), ligase detection-polymerase chain reaction (LD-PCR), ligase detection reaction (LDR), ligation, mutation, nucleic acid amplification technique, nucleotide, oligonucleotide, oncogenes, polymorphism, probe amplification, replication, schizophrenia, single nucleotide polymorphism, SNP, thermocycler, tuberculosis.

Background
  • General: Genes (deoxyribose nucleic acid, or DNA) are considered the building blocks of life because they provide instructions for all cells in the body. Genes, which are located inside cells, control the development and function of an organism by instructing cells to make new molecules (proteins). Proteins are the fundamental components of all living cells and form many substances necessary for the proper functioning of an organism, such as enzymes. An enzyme is a substance that increases the speed of a chemical reaction without being changed in the overall process. Amino acids are molecules that are the building blocks of proteins.
  • DNA is a long, thread-like (double-helix) molecule made up of large numbers of nucleotides, which are the building blocks of DNA and are made of nitrogen bases, sugars, and phosphate. Nitrogen bases are of two types in DNA: purines, such as adenine (A) and guanine (G), and pyrimidines, such as cytosine (C) and thymine (T). Base pairs are two nucleotide sequences located on opposite but complementary DNA strands that are connected by hydrogen bonds. A complementary strand of DNA is a nucleic acid sequence that can form a double-stranded structure by matching base pairs (adenine (A) with thymine (T); guanine (G) with cytosine (C)). For example, a complementary strand for G-T-A-C is C-A-T-G.
  • Mutation: A permanent variation in a DNA sequence of a gene is called a mutation. Mutations that occur in more than one percent of the general population are called polymorphisms. Some mutations and polymorphisms may influence the risk of developing certain disorders or diseases. A point mutation is any change or alteration in a single nucleotide base pair, in which there may be the loss of a nucleotide base, the substitution of one nucleotide base for another, or the insertion of an additional nucleotide base.
  • Polymerase chain reaction (PCR): PCR is an efficient and sensitive laboratory technique to amplify (multiply) a specific sequence of DNA into billions of copies. PCR has revolutionized molecular biology and has become an important tool in molecular diagnostics. Molecular diagnostics is an analytical tool that studies interactions between genes and proteins in a cell. Once it is determined how genes and proteins interact under normal conditions, any changes in how they interact can help to determine how certain diseases or disorders develop. The ligase chain reaction (LCR) and the ligase detection reaction (LDR) techniques were initiated by Barany and coworkers as an alternative to nucleic acid amplification methods like PCR or to enhanced PCR for analyzing mutations that may in turn help in the early identification and treatment of diseases.
  • Ligase chain reaction (LCR): LCR, like PCR, is a technique used to produce multiple copies of DNA (amplification) but differs from PCR in that it amplifies the probe molecule instead of producing fragments of DNA (amplicon) through polymerization of nucleotides. Polymerization is a reaction in which many nucleotides (mononucleotides) are joined to form a polynucleotide (a long chain of nucleotides). Amplicons are small fragments or pieces of DNA that are formed as a result of amplification process. DNA probes are single-stranded DNA sequences with base pairs complementary to the target DNA segment. In this technique, enzymes, such as DNA ligase, are used because DNA ligase was found to have a key role in DNA replication (multiplication).
  • LCR is a technique for target DNA amplification in which an enzyme, DNA ligase, is used to join two complementary oligonucleotide (short sequences of DNA) probes that are bound (ligated) to the target sequence. The ligated product is used as a template to join complementary oligonucleotides which, through repeated processing with enzymes, allow for the production of many copies of DNA. The amplified DNA copies can then be used to determine the presence of the target of interest at the junction of two oligonucleotide probes.
  • Ligase detection reaction (LDR): LDR is a technique used for the identification of any mutation, including point mutations or single nucleotide polymorphisms (SNPs). SNPs are DNA sequence variations that occur when a single nucleotide in the genome sequence is altered. For example, an SNP may change the DNA sequence AAGGCTAA to ATGGCTAA. Here, the first adenine (A) base has been substituted with thymine (T). Since mutations may lead to the development of several diseases, LDR may be used to diagnose diseases caused by a mutation. LDR is similar to LCR, in which amplification is achieved by joining (hybridizing) the target strand with one pair of oligonucleotide primers. An oligonucleotide primer is a sequence of nucleotides, usually of 20-50 bases, that is complementary to a target DNA sequence and serves as a starting point for DNA replication (multiplication). Hybridization is the joining of the probe with the fragment, which allows the target molecule to be analyzed. LDR may be used after the amplification of target DNA by other techniques such as PCR and LCR.

Methods
  • General: Genes (deoxyribose nucleic acid, or DNA) are considered the building blocks of life because they provide instructions for all cells in the body. DNA is a long, thread-like (double-helix) molecule made up of large numbers of nucleotides, which are the building blocks of DNA and are made of nitrogen bases, sugars, and phosphate. Nitrogen bases are of two types in DNA: purines, such as adenine (A) and guanine (G), and pyrimidines, such as cytosine (C) and thymine (T). Long strands of nucleotides form nucleic acids. A complementary strand of DNA is a nucleic acid sequence that can form a double-stranded structure by matching base pairs (adenine (A) with thymine (T); guanine (G) with cytosine (C)). For example, a complementary strand for G-T-A-C is C-A-T-G.
  • RNA (ribonucleic acid) is a nucleic acid that helps in protein synthesis, which is important for the growth and maintenance of the body. RNA is formed under the direction of DNA, and both help to form amino acids, which are the building blocks of protein. Proteins are the fundamental components of all living cells and form many substances which are necessary for the proper functioning of an organism, such as enzymes. An enzyme is a substance that increases the speed of a chemical reaction without being changed in the overall process.
  • Ligase chain reaction (LCR): LCR differs from polymer chain reaction (PCR), an efficient and sensitive laboratory technique to amplify (multiply) a specific sequence of DNA into billions of copies, because it amplifies the probe molecule instead of producing fragments of DNA (amplicon) through polymerization of nucleotides. Polymerization is a reaction in which many nucleotides (mononucleotides) are joined to form a polynucleotide (a long chain of nucleotides). Amplicons are small fragments or pieces of DNA that are formed as a result of amplification process. Two probes are used for each DNA strand and are ligated (bound) together using an enzyme, DNA ligase, to form a single probe. DNA probes are single-stranded DNA sequences with base pairs complementary to the target DNA segment. Similar to PCR, LCR requires a thermocycler to drive the reaction, and each cycle results in a doubling of the target nucleic acid molecule. A thermocycler is an expensive laboratory apparatus used to amplify DNA under controlled temperature conditions. The steps involved in the LCR process are described below.
  • Isolation: Isolation is the initial step in LCR by which the double-stranded DNA from an individual's blood sample is separated from interfering elements, such as other proteins. Several methods may be used for isolation, but all the techniques involve the disruption and breakdown of cells to isolate the DNA.
  • Denaturation and annealing: Denaturation is a process by which the sample is heated, separating the double-stranded DNA into single strands to help in the next process, i.e., annealing. Annealing is a process of heating and cooling the DNA strands, inducing the pairing of probes with single strands of DNA that have complementary sequences. This helps begin the target DNA production.
  • Ligation: In LCR, two complementary oligonucleotide probe pairs that are specific to a DNA target sequence are used. Each probe pair is hybridized to adjacent positions on the template. Hybridization is the joining of the probe with the DNA fragment, which allows the target molecule to be analyzed. The gap or nick created by the joining of two probes is sealed by the enzyme DNA ligase. This helps in the creation of a continuous DNA sequence that can be used to identify the presence of the target molecule. LCR requires a thermocycler to drive the reaction, and each cycle results in a doubling of the target nucleic acid molecule. In a thermocylcer, repeated temperature changes result in the separation of the ligated (bound) units from the target. The separated ligated unit becomes the target for the next cycle or round of ligation. By repeating the above steps through several cycles, there is a rapid exponential accumulation of the specific target fragment of DNA.
  • The probes are attached to radioactive substances (e.g., ethidium bromide) for easy detection of the target sequence. Then, gel electrophoresis is used for the separation of the amplified LCR products, and autoradiography is used to detect the LCR products.
  • Gel electrophoresis: Electrophoresis is a technique that uses electrical current to separate and analyze proteins, DNA, and RNA, by electrical charge. Gel electrophoresis separates the molecules by molecular weight and charge. Molecular weight is the mass (weight) of a molecule relative to the mass of a standard atom, now 12C (the mass of one molecule of carbon is 12.000).
  • The target molecule is analyzed on a polyacrylamide gel electrophoresis (PAGE), and the separated DNA fragments are then paired with complementary sequences of DNA called probes. These probes are tagged with a dye that emits luminescence, facilitating easy detection of the target sequence, thereby identifying the nucleotide base. These fluorescent signals are fed into and analyzed by a computer, identifying the exact sequence of DNA. The whole process is automated, and the resultant DNA sequence is compared with other sequences by various computer programs, thereby spotting the mutations in the sample DNA sequence.
  • Polyacrylamide is a large compound that is formed from several small molecules (polymers) of the chemical acrylamide and is used to form a gel matrix in electrophoresis. Because of its capacity to separate molecules with high resolution, polyacrylamide is also used to separate nucleic acids that are small or those that differ in length by as little as one base pair (two nucleotide sequences located on opposite complementary DNA or RNA strands, connected by hydrogen bonds).
  • Detection: Following electrophoresis, the separated or broken-down target sequences are labeled with a radioactive probe containing a complementary or matching DNA fragment. A radioactive probe is a nucleic acid fragment that is complementary to the target DNA sequence and is attached to radioactive substances (e.g., ethidium bromide), facilitating easier detection. The fragments are detected by a technique called hybridization, which uses a radioactive probe with a complementary DNA sequence. The radioactive DNA is then visualized by autoradiography, a technique where the probes are labeled (attached) with radioactive molecules, which on exposure to X-rays can be visualized. This helps in detecting the exact location of a mutation on the gene.
  • Since prolonged use of radioactive substances may lead to development of cancer, fluorescent (luminescence) labeled probes are used for the identification of a mutation using an automated fluorescent DNA sequencer. A DNA sequencer is an instrument that helps to automate the DNA sequencing process, facilitating the determination of the order of the nucleotide bases in the DNA and detecting any changes that may lead to the development of diseases.
  • Ligase detection reaction (LDR): All of the steps in LDR are similar to those described above in LCR; however, LDR requires only one set of oligonucleotide probes; two sets are required for LCR.
  • Advantages: LCR has certain advantages over PCR. In LCR, few steps are involved in the amplification cycle, thereby reducing the time needed to complete the entire process. Also, PCR requires high-quality DNA because it involves the amplification of large chains of nucleotides, whereas LCR does not, because the target sequence is usually small (36 to 60 nucleotides). Also, LCR can detect variations in DNA sequences that differ only by single base pair, because it has greater capacity (a higher level of detail) to identify changes in the DNA sequence. However, one of the disadvantages of LCR over PCR is that it can only be used to detect single base substitutions that have already been established.

Research
  • General: Ligase chain reaction (LCR) is an amplification (multiplication) technique, and ligase detection reaction (LDR) is a technique used for the identification of any mutation (alteration in a gene). They are similar to PCR, which is an efficient and sensitive laboratory technique to amplify a specific sequence of DNA into billions of copies. Researchers have conducted several studies to improve the methods involved in LCR and LDR.
  • Polymerase chain reaction/ligase detection reaction (PCR/LDR): In the combined method of PCR/LDR, PCR is the amplification step used in LDR, and only one set of adjacent probes is utilized to detect the target sequence. DNA probes are single-stranded DNA sequences with base pairs complementary to the target DNA segment. This method does not produce double-stranded oligonucleotide sequences (short DNA sequences) at the blunt end to ligate (bind), hence it prevents the amplification of sequences that do not contain the target DNA. The blunt end is the end of a DNA molecule where both the strands are of the same length. In ligase chain reaction (LCR), the blunt end DNA strands join together, although the sample may not contain the target DNA sequence. This complex further serves as a template for the next cycle of amplification; therefore the amplified product may not contain the target DNA. To overcome this drawback, PCR/LDR has been developed. The addition of the polymerase enzyme helps in the extension of the strands to fill the gap, allowing the ligation (binding) or incorporation of the target sequence by the ligase enzyme.
  • Gap LCR: Gap LCR is a modified version of LCR wherein the oligonucleotide probes are changed or modified such that they cannot be ligated (joined) if there is no target DNA sequence. The probes are designed in a way that when they are hybridized (joined) to the target DNA, they are separated by a gap (one to several bases) and are not next (adjacent) to each other. The gap is filled by an enzyme, DNA polymerase, which results in the probes that are attached to target DNA being placed adjacent to each other. Then the enzyme DNA ligase helps ligate (join) the pair of probes, forming a product complementary to the original target sequence. This is then used as a template for further cycles of amplication, similar to LCR. This method has higher sensitivity than LCR because it prevents target-independent ligation (ligation without the target DNA). Also gap LCR has the combined effect of both the enzymes, i.e., polymerase and ligase, resulting in an accurate identification of the target of interest. An enzyme is a substance that increases the speed of a chemical reaction without being changed in the overall process. Hybridization is the joining of the probe with the fragment, which allows the target molecule to be analyzed. Sensitivity measures the proportion of true positives (people with diseases) that are correctly identified

Implications
  • Genes (deoxyribose nucleic acid, or DNA) are considered the building blocks of life because they provide instructions for all cells in the body. Genes, which are located inside cells, control the development and function of an organism by instructing cells to make new molecules (proteins). A chromosome is a structure composed of a long DNA molecule and associated proteins that carries part of the hereditary information of an organism.
  • A permanent variation in a DNA sequence of a gene is called a mutation. Genetic changes or mutations that occur in more than 1% of the general population are called polymorphisms. Some mutations and polymorphisms may influence the risk of developing certain disorders or diseases. Detection of a mutation is very important because it helps in the diagnosis of diseases, possibly before the symptoms develop (presymptomatic diagnosis), thereby facilitating early initiation (start) of treatment, achieving better results.
  • Ligase chain reaction (LCR) and ligase detection reaction (LDR) techniques have been developed for the detection of both genetic diseases and diseases caused by infectious agents, such as bacteria and viruses. Some diseases that can be easily identified using LCR or LDR, either alone or in combination with PCR, are described below. PCR is an efficient and sensitive laboratory technique to amplify (multiply) a specific sequence of DNA into billions of copies.
  • Detection of genetic diseases: Genetic diseases are conditions due to abnormalities in genes. LCR and LDR, either alone or in combination with PCR, have been used to identify genetic diseases, such as Leber's hereditary optic neuropathy, hyperkalemic periodic paralysis, cystic fibrosis, and 21-hydroxylase deficiency.
  • Hyperkalemic periodic paralysis: Hyperkalemic periodic paralysis is a disease in which potassium levels are elevated in the blood causing occasional episodes of muscle weakness. The onset occurs in infancy, and attacks are frequent but relatively mild. The disease is caused by a mutation in the sodium channel gene (SCN4A) on chromosome 17q. The mutated gene alters the structure and function of sodium channels in muscle cells, preventing the normal contraction of muscles, which leads to muscle weakness and paralysis. Paralysis is the loss of the power of voluntary movement in a muscle through injury or disease to it or its nerve supply. SCN4A provides instructions for making sodium channels, which play an important role in the ability of cells to generate and transmit electrical signals. LCR, along with PCR, may be used to detect the disease-causing mutations, thereby helping in early diagnosis and treatment, achieving better treatment results.
  • Leber's hereditary optic neuropathy: The optic nerve carries information from the eye to the brain. Leber's hereditary optic neuropathy is an inherited disease in which there is a change in or deterioration of the retinal ganglion cells, which may lead to loss of vision. Retinal ganglion cells are types of nerve cells located near the inner surface of the retina, which is the light-sensitive part of the eye. The disease is caused by a mutation in the mitochondrial DNA, i.e., the energy-producing structures within cells.
  • Cystic fibrosis: Cystic fibrosis (CF), also called mucoviscidosis, is an inherited, life-threatening disorder that causes severe lung damage and nutritional deficiencies (vitamin K, D, and E deficiencies). Patients with CF typically die earlier than individuals who do not have the condition. The average life expectancy of patients with CF is 35 years. Patients with CF inherit two copies of a mutated or defective gene from their parents. Patients who only have one mutated gene and do not experience symptoms of the disorder are called carriers. Although carriers do not have the disorder, they have a 50% chance of passing a copy of the mutated gene on to their children. Hence, a genetic test such as LCR or LDR may be used to detect mutations associated with CF, which may help in early diagnosis and treatment of the disease, in addition to identification of carriers.
  • 21-hydroxylase deficiency: 21-hydroxylase deficiency is also known as congenital adrenal hyperplasia. This is an inherited disorder that affects the adrenal glands, which are located on top of the kidneys and produce hormones that are essential for many functions of the body. A hormone is a chemical released into the body by a gland or tissue that has a specific effect on tissues elsewhere in the body. People with this disorder have a reduced amount of the enzyme 21-hydroxylase, which is important for the production of two hormones, cortisol and aldosterone. Cortisol has various functions, such as protecting the body from stress, maintaining blood sugar levels, and reducing inflammation. Inflammation is the body's response to irritation, injury, infection, chemicals, electricity, heat, cold, or microorganisms, and it is characterized by pain, redness, swelling, and possible loss of function. Aldosterone helps regulate the levels of salt and water in the body by acting on the kidneys, which in turn affects blood pressure. Failure to adequately produce these hormones due to 21-hydroxylase enzyme deficiency affects the activities of the hormones. An enzyme is a substance that increases the speed of a chemical reaction without being changed in the overall process.
  • Detection of cancer: Proto-oncogenes are normal genes that prompt normal cell division by giving cells the signal to divide. Some examples of proto-oncogenes are RAS, WNT, and TRK. When damaged or mutated, proto-oncogenes cause the host cells to divide uncontrollably, possibly leading to the development of cancer. A host cell is any cell within the body that may be affected by mutations or infected by a microorganism (e.g., a virus). LCR and LDR are helpful in detecting these mutations and in diagnosing cancer at an early stage, assisting in beginning early treatment.
  • Detection of bacterial disease-causing organisms (pathogens): LCR or LDR may be used to detect bacteria such as Neisseria gonorrhoeae and Mycobacterium tuberculosis. The organisms are detected by identifying their DNA sequences in samples collected from infected individuals.
  • Neisseria gonorrhoeae: Neisseria gonorrhoeae is a bacterial species that causes gonorrhea and other infections in humans. Gonorrhea is a curable bacterial infection that affects the sex organs. If left untreated, gonorrhea may lead to infertility, i.e., an inability to produce children. Common symptoms of gonorrhea include thick or bloody discharge from the penis or vagina, a painful or burning sensation during urination, frequent urination, and pain during sexual intercourse. Early detection of the disease, by detecting DNA sequences of the disease-causing organism, helps in beginning early appropriate treatment, thereby reducing the complications related to the disease.
  • Mycobacterium tuberculosis: Tuberculosis is a common infectious disease in humans caused by the bacterium Mycobacterium tuberculosis, which may be fatal. This infection spreads through inhalation (breathing in) infected droplets in the air. The bacteria usually attack the lungs but can also damage other parts of the body, such as the lymph nodes, kidneys, and bones. Hence, early identification of the bacterium facilitates the early start of treatment, achieving better results. Lymph nodes are small oval bodies present throughout the body that help in filtering foreign material and fighting infections.
  • Detection of viral pathogens: LCR or LDR may be used to detect viruses such as herpes simplex virus (HSV) and HIV (human immunodeficiency virus).
  • Herpes simplex virus: Herpes is a group of viruses that infect humans. There are two types of herpes simplex viruses: herpes simplex type 1 (HSV-1), also known as a cold sore or fever blister; and herpes simplex type 2 (HSV-2), known as genital herpes. HSV-1, a common virus, is the cause of herpes labialis (fever blisters, cold sores) and involves the lips and inflammation of the gums and mouth. HSV-2 is a sexually transmitted disease (STD), meaning an individual must engage in sexual activity (oral or manual sex or intercourse) in order to transmit or be infected with this virus.
  • HIV: HIV is the virus that potentially causes AIDS (acquired immune deficiency syndrome). HIV primarily attacks the immune system, making the patient extremely vulnerable to opportunistic infections, which occur in people who have weakened immune systems. LCR, along with PCR, is used to detect HIV's genetic material, called ribonucleic acid (RNA). These tests can be used to screen the donated blood supply and to detect very early infections before antibodies have been developed. This test may be performed just days or weeks after exposure to HIV. Antibodies are an important part of the immune system because they identify harmful substances that enter the body and trigger other immune cells to destroy the invading substance.

Limitations
  • One major limitation of LCR is blunt-end ligation, a reaction that joins two DNA double-stranded sequences directly at their blunt ends, although the sample may not contain the target DNA sequence. A blunt end is the end of a DNA molecule where both the strands are of the same length. This complex further serves as template for the next cycle of amplification (multiplication), thereby the amplified product may not contain the target DNA at all. However, certain modifications, like the combination of polymerase with ligase detection reaction, have helped overcome this limitation. The addition of the polymerase enzyme helps in the extension of the strands to fill the gap, allowing ligation (binding) or incorporation of the target sequence by the ligase enzyme.

Safety




Future research
  • Genes (deoxyribose nucleic acid, or DNA) are considered the building blocks of life because they provide instructions for all cells in the body. Genes, which are located inside cells, control the development and function of an organism by instructing cells to make new molecules (proteins). Proteins are the fundamental components of all living cells and form many substances, such as enzymes, which are necessary for the proper functioning of an organism. An enzyme is a substance that increases the speed of a chemical reaction without being changed in the overall process.
  • Amino acids are molecules that are the building blocks of proteins. DNA is a long, thread-like (double-helix) molecule made up of large numbers of nucleotides, the building blocks of DNA made of nitrogenous bases, sugars, and phosphate.
  • Ligase chain reaction (LCR) is an amplification (multiplication) technique, and ligase detection reaction (LDR) is a technique used for the identification of any mutation. A permanent variation in a DNA sequence of a gene is called a mutation. These techniques are similar to polymerase chain reaction (PCR), which is an efficient and sensitive laboratory technique to amplify (multiply) a specific sequence of DNA into billions of copies. Several studies are being conducted using LCR and LDR to identify more diseases due to mutations.
  • Schizophrenia and cytosolic phospholipase A2 (cPLA2) family genes: Gene families include a group of genes related by sequence similarity, i.e., the DNA sequences are similar in the families. Genes belonging to the same family provide instructions for making proteins that have a similar function and structure. The cPLA2 gene family provides instructions for making an enzyme known as phospholipase A2, which is important for the breakdown of a particular type of fat known as a phospholipid. Schizophrenia is a brain disorder that causes patients to suffer from delusions and hallucinations, making it difficult for a person to tell the difference between real and unreal experiences, to think logically, to have normal emotional responses to others, and to behave normally in social situations. Researchers are conducting studies using PCR-LDR to examine the relationship between polymorphisms in cPLA2 family genes and schizophrenia. Genetic changes or mutations that occur in more than 1% of the general population are called polymorphisms. The results of these studies indicate that there may be an association between cPLA2 and schizophrenia. This finding may help in the early detection of the disease, aiding in the early start of treatment, thereby achieving good treatment results.
  • Coronary artery disease (CAD): CAD, also known as coronary heart disease (CHD), occurs when the coronary arteries (the blood vessels that supply oxygen-rich blood to the heart muscle) gradually become narrowed or blocked by plaque deposits (a combination of fatty material, calcium, scar tissue, and proteins). Interleukin 18 (IL-18), a cytokine that promotes plaque formation, is associated with the occurrence of various cardiac (heart) complications. Cytokines are a group of proteins that help regulate the immune system. They facilitate communication among immune cells, which fight against harmful substances, such as bacteria that enter the body. Researchers have detected polymorphisms in the IL-18 gene by using PCR-LDR and have found that it results in the development of atherosclerosis, in which plaque builds up inside the arteries that carry blood to the heart and which can lead to stroke (lack of oxygen) in the brain. The identification of the mutation that is responsible for the development of the disease may help in developing strategies to prevent or treat the disease. This may also help in early detection of the disease since researchers know which gene is responsible for the disease.

Author information
  • This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

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