February is American Heart Month. Sponsored by the American Heart Association, American Heart Month is a time to battle cardiovascular disease and educate people on what they can do to live heart-healthy lives. Heart disease, including stroke, is the leading cause of death for men and women in the United States.

How much do you know about the condition of your heart? Heart health awareness typically focuses on heart disease in older adults caused by an unhealthy diet and a lack of exercise. But what if you could be at risk for cardiac arrest and sudden death even though you are young and in shape?

Image credit: Heart arrhythmia via Shutterstock

Long QT syndrome (LQTS) is one of several sudden arrhythmia death syndromes, a class of conditions affecting the heart’s rhythm. People can be born with an inherited form of the syndrome or acquire it during their life. LQTS can cause sudden, uncontrollable, dangerous heartbeats in response to exercise or stress. LQTS can arise from mutation of one of several genes, including Potassium Channel, Voltage-gated, KQT-like Subfamily, Member 1 (KCNQ1); Potassium Channel, Voltage-gated, Subfamily H, Member 2 (KCNH2); and Sodium Channel, Voltage-gated, Type V, Alpha Subunit (SCN5A).

LQTS is common; approximately one in every 2,500 people has the disorder [1]. Some people don’t discover they have LQTS until the sudden unexplained death of a family member. However, if identified, LQTS can be treated with medications, limited physical activity, or, in some cases, medical devices or surgery [2].

Dr. Brian Delisle, a faculty member of the University of Kentucky’s College of Medicine, is studying the genetic form of LQTS in order to identify new treatments. According to Delisle, there are several types of the genetic form of LQTS, each caused by a different gene mutation. One form of LQTS syndrome, LQT2 (which involves mutations of the human ether-a-go-go related gene (hERG), also known as KCNH2), is caused by a mutation in a gene that codes for potassium channels in the heart’s cells. The mutation prevents the potassium channels from being transported to their proper place at the cell’s surface. As a result, the potassium channels cannot function properly.

In a recent study published in the American Journal of Physiology Cell Physiology, researchers from Delisle’s laboratory found that a distinct cellular compartment in cardiac myocytes (heart cells) negatively regulates the production and movement of LQT2 [3]. Delisle said:

We do have a series of drugs that can correct this … in cell systems. But the problem right now is that most of the drugs that do this actually cause the acquired form of Long QT.

Delisle hopes that by better understanding the mechanism preventing the proper transport of the potassium channels to the cell’s surface, other therapeutic approaches can be identified to correct this problem.

About the author: Julianne Wyrick is a senior biochemistry major at Asbury University. A 2011 Kentucky Academy of Sciences award winner for scientific research, following graduation Julianne plans to enter a health and medical journalism graduate program.

References

1. Long QT Syndrome. Sudden Arrhythmia Death Syndrome (SADS) Foundation. Accessed 2012 Jan 28.
2. Long QT Syndrome. Mayo Clinic. Accessed 2012 Jan 28.
3. Smith et al. Trafficking-deficient hERG K? channels linked to long QT syndrome are regulated by a microtubule-dependent quality control compartment in the ER. Am J Physiol Cell Physiol. 2011 Jul;301(1):C75-85. Epub 2011 Apr 13.
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Sickle cell disease is a recessive genetic disorder caused by a single base mutation in the gene for hemoglobin, beta locus (HBB). Hemoglobin is responsible for transporting oxygen throughout the body. People living with sickle cell disease have two copies of an altered gene that produces sickle hemoglobin instead of normal adult hemoglobin. Sickle hemoglobin changes shape after releasing its oxygen, causing the red blood cell to become stiff, misshapen and sticky, and slowing blood flow to tissues. This process damages organs and causes pain.

Susan B. Shurin, M.D., acting director of the NIH’s National Heart, Lung, and Blood Institute, which co-funded the study, said:

This discovery provides an important new target for future therapies in people with sickle cell disease. More work is needed before it will be possible to test such therapies in people, but this study demonstrates that the approach works in principle.

Researchers at Harvard Medical School in Boston and the University of Texas at Austin corrected sickle cell disease in mice that had been bred to have the inherited blood disorder. The National Heart, Lung, and Blood Institute, the National Cancer Institute, and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) — all part of the NIH — funded the research. The results of the study were recently published in the online edition of the journal Science [1].

The study tested a new approach to increasing the production of a third form of hemoglobin — fetal hemoglobin. Production of fetal hemoglobin predominates before birth, but turns off thereafter as adult hemoglobin production takes over. People with sickle cell disease are unable to make normal adult hemoglobin, and instead make sickle hemoglobin starting in infancy.

An elevated level of fetal hemoglobin within the red blood cell reduces the tendency of sickle hemoglobin to change the shape of red blood cells. Considerable NIH- supported research has shown that the drug hydroxyurea increases production of fetal hemoglobin and reduces the number of pain crises and other complications of sickle cell disease in adults and children. However, not all patients respond well to hydroxyurea, and adverse side effects are a concern.

The current study explores a more targeted approach to increasing fetal hemoglobin production. It builds upon earlier studies by Stuart Orkin, M.D., and his team at Harvard Medical School, Children’s Hospital of Boston, and the Howard Hughes Medical Institute, Boston, which discovered that a protein called B-cel CLL/Lymphoma 11A (BCL11A) normally suppresses the production of fetal hemoglobin soon after birth [2]. The researchers viewed the BCL11A protein as a target for therapy and decided to see what would happen if they blocked production of the protein.

Griffin P. Rodgers, M.D., M.A.C.P., director of NIDDK, said:

This important advance in the battle against sickle cell disease is another outstanding example of how great things can happen when work proceeds from bench to bedside, and back to the bench. We hope that one day, this discovery and any that build upon it will translate into a viable treatment option for those suffering from this devastating illness.

The current paper details how the research team silenced the mouse gene that produces the BCL11A protein in mice with sickle cell disease. Silencing the gene turned off production of the BCL11A protein and allowed the adult mice to continue to produce fetal hemoglobin. It appears to have eliminated disease symptoms without affecting other aspects of blood production.

Approximately 100,000 Americans live with sickle cell disease. It is most prevalent in people of African, Hispanic, Mediterranean, and Middle Eastern descent. There is no widely available cure for sickle cell disease. Bone marrow transplants have cured some patients, but the treatment is not without risk and most patients do not have relatives who can donate compatible and healthy bone marrow to them.

Source: NIH News

References

1. Xu et al. Correction of Sickle Cell Disease in Adult Mice by Interference with Fetal Hemoglobin Silencing. Science. 2011 Oct 13. [Epub ahead of print]
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2. Sankaran et al. Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science. 2008 Dec 19;322(5909):1839-42.
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The cytochrome P450 enzyme superfamily (abbreviated as CYP) are the major enzymes involved in drug metabolism and bioactivation. Cytochrome P450, subfamily IIIA, polypeptide 4 (CYP3A4) is the primary CYP expressed in adult human liver. It is both continuously expressed as well as activated by a variety of clinically used drugs. CYP3A4 activity is known to show a significant variability not only between different people but also within the same person at different times. The reason for this variability is unknown.

The goal of the present study was to test the hypothesis that plasma concentrations of three immunosuppressant drugs — tacrolimus, sirolimus and cyclosporine — show seasonal variations associated with increased CYP34A4 enzyme via vitamin D. These drugs were used because they are dependent on the CYP3A4 metabolic pathway and most patients taking these drugs use them for long periods of time and require repeated concentration determinations.

The researchers reviewed almost 70,000 analyses from patients who had undergone regular monitoring of the levels of drugs in their blood. They found that samples collected during the summer (July-September) had significantly lower dose-corrected concentrations of tacrolimus and sirolimus compared to those collected during the winter (January – March). In contrast, no change was detected in cyclosporine concentrations.

A more detailed analysis found that the concentrations of tacrolimus and sirolimus vary throughout the year, closely reflecting the changes in the level of vitamin D in the body. The body depends on sunlight to form vitamin D. The highest levels of vitamin D in patients taking part in the study were reached when the levels of the drugs were lowest.

Although the results are correlative, not causal, scientists think the connection between sunlight, vitamin D and the bioavailability of sirolimus and tacrolimus arises from the activation by vitamin D of the liver detoxification system, specifically by increasing the amount CYP3A4. In turn, CYP3A4 is responsible for the breakdown of tacrolimus and sirolimus.

Jonatan Lindh at the Karolinska Institutet Department of Laboratory Medicine and lead author of the study said [2]:

If the breakdown capacity increases, then higher doses of a drug are normally required in order to achieve the same effect. More research will be needed to confirm the results, but CYP3A4 is considered to be the most important enzyme in drug turnover in the body, and the results may have significance for many drugs.

Just three years ago, we reported on the International Serious Adverse Events Consortium (SAEC), which announced plans to identify genetic markers that predicted drug-related serious adverse events. The results of the current study suggest that individual differences in the effects of drugs is even more intricate than just genetics alone.

References

1. Lindh et al. Seasonal variation in blood drug concentrations and a potential relationship to vitamin d. Drug Metab Dispos. 2011 May;39(5):933-7. Epub 2011 Feb 24.
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2. Sunlight can influence the breakdown of medicines in the body. Karolinska Institutet. 2011 Mar 9.

It has long been known that peanut allergies are heritable, but the gene responsible for this heritability was unknown. Filaggrin is a protein that is expressed primarily in the skin, where it binds to keratin and plays an important role in forming the protective and impenetrable barrier that makes skin such a vital organ. Mutations in the filaggrin gene have already been identified as risk factors for eczma, asthma and other allergies, which is what prompted Drs. Sara Brown at the University of Dundee in the UK and Yuka Asai at McGill University Health Centre in Montreal, Quebec, Canada, and colleagues to consider it as a candidate gene for peanut allergies.

The researchers analyzed blood or saliva from 71 white English, Dutch, and Irish people known to have peanut allergies based on an oral challenge and 1000 healthy English controls. To confirm their results, they repeated the study with 390 white Canadians who had peanut allergies and 891 white Canadian healthy controls. They looked for loss-of-function mutations — those that completely inactivate the protein — in the filaggrin gene (FLG) that are most prevalent in the European population. They found that these mutations are “strongly and significantly associated with peanut allergy.” Twenty percent of the people with peanut allergies harbored a loss-of-function mutation in the filaggrin gene in both the European and Canadian populations, compared to 5 – 10% of the control populations.

It is still unclear how nonfunctional filaggrin might allow peanut allergies to arise. Eczma is a hypersensitivity reaction in the skin that results in inflammation, and is thus very much like an allergy. It has been suggested that impairment of the epidermal barrier — as would occur if filaggrin function is disrupted — could allow allergens to penetrate into the body, causing a local inflammatory response like eczma as well as a more systemic response like asthma. Studies performed in mouse models support this hypothesis. This explains tactile peanut allergies, and to make the story even neater, eczma is a known risk factor for peanut allergies. In fact, eczma is a stronger risk factor than these loss-of-function mutations in the filaggrin gene. As for oral exposure to peanuts, some patients with eczma have increase intestinal permeability … but it is not yet known if filaggrin plays a role here. Filaggrin has not been found in the gastrointestinal tract, but it is present in the oral mucosa and possibly as far down as the esophagus.

The authors suggest that these mutations might be associated with other food allergies. As the “most significant genetic risk for peanut allergy that has been identified to date,” looking into that possibility certainly seems warranted.

Researchers at the North Carolina Agricultural and Technical State University have recently developed an enzymatic treatment that reduces two of the most potent peanut allergens in roasted peanut kernels, Ara h 1 and Ara h 2 [2]. Ninety percent of those with peanut allergies react to these two proteins. Jainmei Yu, who has been working on developing hypo-allergenic peanuts since 2005, plans to begin clinical trials as a first step of getting them. Hopefully they will be successful, and peanut butter and jelly sandwiches will become a school lunchroom staple once again.

References

1. Brown et al. Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy. J Allergy Clin Immunol. 2011 Mar;127(3):661-7.
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2. Yua et al. Enzymatic treatment of peanut kernels to reduce allergen levels. Food Chemistry. 2011 Aug;127(3):1014-22.

“The pilot studies of the 1000 Genomes Project laid a critical foundation for studying human genetic variation,” said Richard Durbin, Ph.D., of the Wellcome Trust Sanger Institute and co-chair of the consortium. “These proof-of-principle studies are enabling consortium scientists to create a comprehensive, publicly available map of genetic variation that will ultimately collect sequence from 2,500 people from multiple populations worldwide and underpin future genetics research.”

Genetic variation between people refers to differences in the order of the chemical units — called bases — that make up DNA in the human genome. These differences can be as small as a single base being replaced by a different one “” which is called a single nucleotide polymorphism (abbreviated SNP) — or is as large as whole sections of a chromosome being duplicated or relocated to another place in the genome. Some of these variations are common in the population and some are rare. By comparing many individuals to one another and by comparing one population to other populations, researchers can create a map of all types of genetic variation.

The 1000 Genomes Project’s aim is to provide a comprehensive public resource that supports researchers aiming to study all types of genetic variation that might cause human disease. The project’s approach goes beyond previous efforts in capturing and integrating data on all types of variation, and by studying samples from numerous human populations with informed consent allowing free data release without restriction on use. Already, these data have been used in studies of the genetic basis for disease.

“By making data from the project freely available to the research community, it is already impacting research for both rare and common diseases,” said David Altshuler, M.D., Ph.D., deputy director of the Broad Institute of Harvard and MIT, and a co-chair of the project. “Biotech companies have developed genotyping products to test common variants from the project for a role in disease. Every published study using next-generation sequencing to find rare disease mutations, and those in cancer, used project data to filter out variants that might obscure their results.”

The project has studied populations with European, West African and East Asian ancestry. Using the newest technologies for sequencing DNA, the project’s nine centers sequenced the whole genome of 179 people and the protein-coding genes of 697 people. Each region was sequenced several times, so that more than 4.5 terabases (4.5 million million base letters) of DNA sequence were collected. A consortium involving academic centers on multiple continents and technology companies that developed the sequencing equipment carried out the work.

To process these data required many technical and computational innovations, including standardized ways to organize, store, analyze and share DNA sequencing data. Launched in 2008, the 1000 Genomes Project started with three pilot projects to develop, evaluate and compare strategies for producing a catalogue of genetic variations. Funded through numerous mechanisms by foundations and national governments, the 1000 Genomes Project will cost some $120 million over five years, ending in 2012.

When the work began, sequencing was very expensive, so the project began with two approaches aimed at increasing efficiency: One strategy — called “low pass” — combines partial data from many people; the second only focused on the part of the genome that encodes protein-coding genes. By comparing these strategies to “gold standard” data produced at great completeness and accuracy, the project was able to show that both the alternative approaches work well and have complementary strengths. Researchers will use both strategies in the full-scale project because, although sequencing costs have decreased, it is still relatively expensive.

“We have shown for the first time that a new approach to sequencing — low coverage of many samples — works efficiently and well,” said Gil McVean, Ph.D., professor of statistical genetics at the University of Oxford. “This proof of principle is now being applied not only in the 1000 Genomes Project, but in disease research, as well.”

The resulting map of human genetic variation includes about 15 million SNPs, 1 million short insertion/deletion changes, and more than 20,000 structural variations. Many of the genetic variants had previously been identified, but more than half were new. The project’s database contains more than 95 percent of the currently measurable variants found in any individual, and continuing work will eventually identify more than 99 percent of human variants.

Richard Gibbs, Ph.D., director of the Human Genome Sequencing Center at the Baylor College of Medicine (one of the projects sequencing centers) said: “What really excites me about this project is the focus on identifying variants in the protein-coding genes that have functional consequences. These will be extremely useful for studies of disease and evolution.”

The improved map produced some surprises. For example, the researchers discovered that on average, each person carries between 250 and 300 genetic changes that would cause a gene to stop working normally, and that each person also carried between 50 and 100 genetic variations that had previously been associated with an inherited disease. No human carries a perfect set of genes. Fortunately, because each person carries at least two copies of every gene, individuals likely remain healthy, even while carrying these defective genes, if the second copy works normally.

In addition to looking at variants that are shared among many people, the researchers also investigated in detail the genomes of six people: two mother-father-daughter nuclear families. By finding new variants present in the daughter but not the parents, the team was able to observe the precise rate of mutations in humans, showing that each person has approximately 60 new mutations that are not in either parent.

With the completion of the pilot phase, the 1000 Genomes Project has moved into full-scale studies in which 2,500 samples from 27 populations will be studied over the next two years. Data from the pilot studies and the full-scale project are freely available on the project website, http://www.1000genomes.org/.

Researchers studying specific illnesses, such as heart disease or cancer, use maps of genetic variation to help them identify genetic changes that may contribute to the illnesses. Over the last five years, the first generation of such studies (called genome-wide association studies or GWAS) have been based on an earlier map of genetic variation called the HapMap. Built using older technology, HapMap lacks the completeness and detail of the 1000 Genomes Project.

“The 1000 Genomes Project map fills in the gaps between the HapMap landmarks, helping researchers identify all candidate genes in a region associated with a disease,” said Lisa Brooks, Ph.D., program director for the Genetic Variation Program at the National Human Genome Research Institute, a part of the National Institutes of Health. “Once a disease-associated region of the genome is identified, experimental studies must be done to identify which variants, genes and regulatory elements cause the increased disease risk. With the new map, researchers can just look up all the candidate genes and almost all of the variants in the database, saving them many steps in finding the causes.”

Organizations that committed major support to the project include: 454 Life Sciences, a Roche company, Branford, Conn.; Life Technologies Corporation, Carlsbad, Calif.; BGI-Shenzhen, Shenzhen, China; Illumina Inc., San Diego; the Max Planck Institute for Molecular Genetics, Berlin, Germany; the Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; and the National Human Genome Research Institute, Bethesda, Md., which supports the work being done by Baylor College of Medicine, Houston, Texas; the Broad Institute, Cambridge, Mass.; and Washington University, St. Louis, Missouri. Researchers at many other institutions are also participating in the project including groups in Barbados, Canada, China, Colombia, Finland, the Gambia, India, Malawi, Pakistan, Peru, Puerto Rico, Spain, the UK, the US, and Vietnam. Additional information about the project, including a list of all participants and organizations, can be found at http://www.1000genomes.org/.

Source: NIH News

Although the root cause(s) of stuttering remain unknown, evidence has accumulated from twin and adoption studies that genetics plays a role. Dennis Drayna, a geneticist at the National Institute on Deafness and other Communication Disorders (NIDCD), undertook a study to identify the genes involved in the disorder with the ultimate goal to elucidate poorly defined neural structures and functions regulating human speech. Results from the study were reported recently in the New England Journal of Medicine [1].

The study focused on a Pakistani family in whom previous work had determined that stuttering was linked to the long arm of chromosome 12 (chromosome 12q). In addition to the affected and unaffected members of these families, the study also included 123 Pakistani stutterers who were unrelated and 270 stutterers from the United States and England. Children under the age of eight were excluded, as they often recover from stuttering, as were people with neurologic or psychiatric symptoms. The control group (non-stutterers) consisted of 96 Pakistanis and 276 North American whites.

By sequencing the DNA from chromosome 12q in seven Pakistani stutterers and three Pakistani non-stutterers they homed in on a region of 10 Megabases, containing 87 genes, that was linked to stuttering. The mutations that cosegregated most closely with stuttering — those that were found most often in stutterers — were in a gene called GNPTAB. This gene encodes GlcNAc-phosphotransferase, an enzyme involved in targeting lysosomal enzymes. Like all proteins, lysosomal enzymes are synthesized in the cytoplasm of the cell. GlcNAc-phosphotransferase tags them with mannose-6-phosphate, a sugar molecule that tells the cellular trafficking system to send them to the lysosome. The most common mutation in stutterers from the Asian subcontinent was one that substitutes lysine, an alkaline amino acid, for glutamic acid at position 1,200 in the protein. This amino acid is highly conserved; all vertebrates normally have a glutamic acid at this position, implying that it is important.

Lysosomes are the cellular organelles often likened to a garbage disposal. The enzymes in the lysosome are responsible for degrading extra and expended cellular components, food particles and any viruses and bacteria the cell may have picked up.

After identifying this mutation, the researchers looked at other genes involved in the same pathway — those encoding other proteins responsible for targeting lysosomal enzymes. They found mutations in two other such genes, GlcNAc-1-phosphotransferase subunit gamma (GNPTG) and N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase (NAGPA) in unrelated North American and British stutterers. These mutations were never seen in non-stuttering controls.

Mutations in GNPTAB and GNPTG are known to be associated with the rare inherited lysosomal storage disorders mucolipidosis (ML) types II and III. They are so named because cellular components cannot be degraded properly, and instead end up getting stored in the lysosome. These disorders are characterized by developmental delay; joint, heart, liver, and skeletal system problems; and often, speech deficits. Interestingly, GNPTG is highly expressed in areas of the mouse brain known to be associated with emotion: the hippocampus and cerebellum. Emotional state can definitely impact stuttering. Mutations in NAGPA have never been associated with any human malady.

How, then, did the stutterers get off relatively easy — if they have mutations in the same genes, why don’t they have the same problems? ML disorders are inherited in a recessive manner, so are caused by having two copies of the mutated gene. These stutterers have one mutated copy and one normal copy. Moreover, the mutations they found — which are not present in people with ML II or III — result in an altered protein, whereas those that cause ML II and III yield a truncated protein. In addition, they found mutant GNPTAB in members of the Pakistani family who did not stutter. This indicates that the mutation has incomplete penetrance, meaning that it is possible to have the mutated gene, but not necessarily stutter. The mutation increases the risk of stuttering rather than causing it directly in every case.

Approximately 1% of Americans — roughly 3 million people — stutter. In their future work, Dr. Drayna and colleagues intend to find the percentage of the general population with one of these mutations, and to figure out exactly how mutations in these enzymes impact the enzyme’s activity.

For more information on theNational Institute on Deafness and other Communication Disorders, please visit www.nidcd.nih.gov.

References

1. Kang et al. Mutations in the lysosomal enzyme-targeting pathway and persistent stuttering. N Engl J Med. 2010 Feb 25;362(8):677-85. Epub 2010 Feb 10.
   View Abstract

Currently, more than 1,600 genetic tests are available to patients and consumers, but there is no single public resource that provides detailed information about them. GTR is intended to fill that gap.

The overarching goal of the GTR is to advance the public health and research into the genetic basis of health and disease. As such, the registry will have several key functions:

• Encourage providers of genetic tests to enhance transparency by publicly sharing information about the availability and utility of their tests
• Provide an information resource for the public, including researchers, health care providers and patients, to locate laboratories that offer particular tests
• Facilitate genomic data-sharing for research and new scientific discoveries

NIH Director Francis S. Collins, M.D., Ph.D., said:

The need for this database reflects how far we have come in the last 10 years. The registry will help consumers and health care providers determine the best options for genetic testing, which is becoming more and more common and accessible. Our combined expertise in biomedical research and managing such large databases makes NIH the ideal home for the registry.

The GTR project will be overseen by the NIH Office of the Director. The National Center for Biotechnology Information (NCBI), part of the National Library of Medicine at NIH, will be responsible for developing the registry, which is expected to be available in 2011. GTR genetic test data will be integrated with information in other NIH/NCBI genetic, scientific, and medical databases to facilitate the research process. This integration will allow scientists to make, more easily and effectively, the kinds of connections that ultimately lead to discoveries and scientific advances.

During the development process, NIH will engage with stakeholders — such as genetic test developers, test kit manufacturers, health care providers, patients, and researchers — for their insights on the best way to collect and display test information. In addition, other federal agencies, including the Food and Drug Administration and the Centers for Medicare and Medicaid Services, will be consulted.

More information about the Genetic Testing Registry and NCBI is available at: http://www.ncbi.nlm.nih.gov/gtr/.

Source: NIH News

“A substantial body of scientific evidence indicates that inflammatory hormones may play a significant role in the labor process,” said Alan E. Guttmacher, M.D., acting director of the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). “The current findings add evidence that individual genetic variation in that response may account for why preterm labor occurs in some pregnancies and not in others.”

Non-coding RNAs include a class of molecules called microRNAs (miRNAs or miRs). MicroRNAs are highly expressed in normal tissues and are being found to have critical roles in gene regulatory processes during cellular development and differentiation. MicroRNAs are small ncRNAs ~21-nucleotides long that regulate gene expression at the post-transcriptional level. MicroRNAs function by binding target mRNA molecules and either inhibiting translation into protein or targeting them for degradation. Abnormal microRNA expression has been linked to many human diseases, including schizophrenia, autism and cancer.

Click for a larger image

MicroRNAs (miRNAs) are transcribed from DNA to produce a stem-loop structure containing a primary transcript called a pri-miRNA that ranges in size from hundreds of nucleotides to tens of kilobases. In the nucleus, pri-miRNAs are processed to shorter ~70 nucleotide hairpin precursor miRNAs known as pre-miRNAs by a multiprotein complex called the Microprocessor complex, which consist of the core components Drosha, an RNase III enzyme, and Pasah, a double-stranded RNA binding protein. The pre-miRNA is transported to the cytoplasm and processed by another RNase III enzyme, Dicer, to produce mature ~22-nucleotide miRNA:miRNA duplexes. A ribonucleoprotein complex called miRSC is then assembled with one strand of the miRNA duplex called the guide strand (purple in figure). Depending upon partial or exact complementarity to messenger RNA, miRISC mediates inhibition of translation or messenger RNA degradation [3].

MicroRNAs represent exciting cutting-edge biomarkers for present and future clinical use that are actively being investigated. Currently, there are three commercially available molecular diagnostic tests for cancer based on microRNAs, all from Rosetta Genomics. In addition, microRNAs have potential application as prognostic indicators and therapeutic targets.

For more information on microRNAs, see:

• miRNA Blog
• You’d Prefer An Argonaute

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References

1. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. ENCODE Project Consortium. Nature. 2007 Jun 14;447(7146):799-816.
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2. Washietl et al. Structured RNAs in the ENCODE selected regions of the human genome. Genome Res. 2007 Jun;17(6):852-64.
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3. Filipowicz et al. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet. 2008 Feb;9(2):102-14.
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