Posts tagged genetics
Articles and news from the latest research reports.
(Image caption: LB1 in three different views to illustrate facial asymmetry. A is the actual specimen, B is the Right side doubled at the midline and mirrored, and C is the left side doubled and mirrored. Differences in left and right side facial architectures are apparent, and illustrate growth abnormalities of LB1. Credit: A, E. Indriati, B and C, D.W. Frayer)
Flores bones show features of Down syndrome, not a new “hobbit” human
In October 2004, excavation of fragmentary skeletal remains from the island of Flores in Indonesia yielded what was called “the most important find in human evolution for 100 years.” Its discoverers dubbed the find Homo floresiensis, a name suggesting a previously unknown species of human.
Now detailed reanalysis by an international team of researchers including Robert B. Eckhardt, professor of developmental genetics and evolution at Penn State, Maciej Henneberg, professor of anatomy and pathology at the University of Adelaide, and Kenneth Hsü, a Chinese geologist and paleoclimatologist, suggests that the single specimen on which the new designation depends, known as LB1, does not represent a new species. Instead, it is the skeleton of a developmentally abnormal human and, according to the researchers, contains important features most consistent with a diagnosis of Down syndrome.
"The skeletal sample from Liang Bua cave contains fragmentary remains of several individuals," Eckhardt said. "LB1 has the only skull and thighbones in the entire sample."
No substantial new bone discoveries have been made in the cave since the finding of LB1.
Initial descriptions of Homo floresiensis focused on LB1’s unusual anatomical characteristics: a cranial volume reported as only 380 milliliters (23.2 cubic inches), suggesting a brain less than one third the size of an average modern human’s and short thighbones, which were used to reconstruct a creature standing 1.06 meters (about 3.5 feet tall). Although LB1 lived only 15,000 years ago, comparisons were made to earlier hominins, including Homo erectus and Australopithecus. Other traits were characterized as unique and therefore indicative of a new species.
A thorough reexamination of the available evidence in the context of clinical studies, the researchers said, suggests a different explanation.
The researchers report their findings in two papers published today (Aug. 4) in the Proceedings of the National Academy of Sciences (1, 2).
In the first place, they write, the original figures for cranial volume and stature are underestimates, “markedly lower than any later attempts to confirm them.” Eckhardt, Henneberg, and other researchers have consistently found a cranial volume of about 430 milliliters (26.2 cubic inches).
"The difference is significant, and the revised figure falls in the range predicted for a modern human with Down syndrome from the same geographic region," Eckhardt said.
The original estimate of 3.5 feet for the creature’s height was based on extrapolation combining the short thighbone with a formula derived from an African pygmy population. But humans with Down syndrome also have diagnostically short thighbones, Eckhardt said.
Though these and other features are unusual, he acknowledged, “unusual does not equal unique. The originally reported traits are not so rare as to have required the invention of a new hominin species.”
Instead, the researchers build the case for an alternative diagnosis: that of Down syndrome, one of the most commonly occurring developmental disorders in modern humans.
"When we first saw these bones, several of us immediately spotted a developmental disturbance," said Eckhardt, "but we did not assign a specific diagnosis because the bones were so fragmentary. Over the years, several lines of evidence have converged on Down syndrome."
The first indicator is craniofacial asymmetry, a left-right mismatch of the skull that is characteristic of this and other disorders. Eckhardt and colleagues noted this asymmetry in LB1 as early as 2006, but it had not been reported by the excavating team and was later dismissed as a result of the skull’s being long buried, he said.
A previously unpublished measurement of LB1’s occipital-frontal circumference — the circumference of the skull taken roughly above the tops of the ears — allowed the researchers to compare LB1 to clinical data routinely collected on patients with developmental disorders. Here too, the brain size they estimate is within the range expected for an Australomelanesian human with Down syndrome.
LB1’s short thighbones not only match the height reduction seen in Down syndrome, Eckhardt said, but when corrected statistically for normal growth, they would yield a stature of about 1.26 meters, or just over four feet, a figure matched by some humans now living on Flores and in surrounding regions.
These and other Down-like characteristics, the researchers state, are present only in LB1, and not in the other Liang Bua skeletal remains, further evidence of LB1’s abnormality.
"This work is not presented in the form of a fanciful story, but to test a hypothesis: Are the skeletons from Liang Bua cave sufficiently unusual to require invention of a new human species?" Eckhardt said.
"Our reanalysis shows that they are not. The less strained explanation is a developmental disorder. Here the signs point rather clearly to Down syndrome, which occurs in more than one per thousand human births around the world."
Scientists find 6 new genetic risk factors for Parkinson’s
Using data from over 18,000 patients, scientists have identified more than two dozen genetic risk factors involved in Parkinson’s disease, including six that had not been previously reported. The study, published in Nature Genetics, was partially funded by the National Institutes of Health (NIH) and led by scientists working in NIH laboratories.
"Unraveling the genetic underpinnings of Parkinson’s is vital to understanding the multiple mechanisms involved in this complex disease, and hopefully, may one day lead to effective therapies," said Andrew Singleton, Ph.D., a scientist at the NIH’s National Institute on Aging (NIA) and senior author of the study.
Dr. Singleton and his colleagues collected and combined data from existing genome-wide association studies (GWAS), which allow scientists to find common variants, or subtle differences, in the genetic codes of large groups of individuals. The combined data included approximately 13,708 Parkinson’s disease cases and 95,282 controls, all of European ancestry.
The investigators identified potential genetic risk variants, which increase the chances that a person may develop Parkinson’s disease. Their results suggested that the more variants a person has, the greater the risk, up to three times higher, for developing the disorder in some cases.
"The study brought together a large international group of investigators from both public and private institutions who were interested in sharing data to accelerate the discovery of genetic risk factors for Parkinson’s disease," said Margaret Sutherland, Ph.D., a program director at the National Institute of Neurological Disorders and Stroke (NINDS), part of NIH. "The advantage of this collaborative approach is highlighted in the identification of pathways and gene networks that may significantly increase our understanding of Parkinson’s disease."
To obtain the data, the researchers collaborated with multiple public and private organizations, including the U.S. Department of Defense, the Michael J. Fox Foundation, 23andMe and many international investigators.
Affecting millions of people worldwide, Parkinson’s disease is a degenerative disorder that causes movement problems, including trembling of the hands, arms, or legs, stiffness of limbs and trunk, slowed movements and problems with posture. Over time, patients may have difficulty walking, talking, or completing other simple tasks. Although nine genes have been shown to cause rare forms of Parkinson’s disease, scientists continue to search for genetic risk factors to provide a complete genetic picture of the disorder.
The researchers confirmed the results in another sample of subjects, including 5,353 patients and 5,551 controls. By comparing the genetic regions to sequences on a state-of-the-art gene chip called NeuroX, the researchers confirmed that 24 variants represent genetic risk factors for Parkinson’s disease, including six variants that had not been previously identified. The NeuroX gene chip contains the codes of approximately 24,000 common genetic variants thought to be associated with a broad spectrum of neurodegenerative disorders.
"The replication phase of the study demonstrates the utility of the NeuroX chip for unlocking the secrets of neurodegenerative disorders," said Dr. Sutherland. "The power of these high tech, data-driven genomic methods allows scientists to find the needle in the haystack that may ultimately lead to new treatments."
Some of the newly identified genetic risk factors are thought to be involved with Gaucher’s disease, regulating inflammation and the nerve cell chemical messenger dopamine as well as alpha-synuclein, a protein that has been shown to accumulate in the brains of some cases of Parkinson’s disease. Further research is needed to determine the roles of the variants identified in this study.
Schizophrenia’s genetic skyline rising
The largest genomic dragnet of any psychiatric disorder to date has unmasked 108 chromosomal sites harboring inherited variations in the genetic code linked to schizophrenia, 83 of which had not been previously reported. By contrast, the “skyline” of such suspect variants associated with the disorder contained only 5 significant peaks in 2011. By combining data from all available schizophrenia genetic samples, researchers supported by the National Institutes of Health powered the search for clues to the molecular basis of the disorder to a new level.
“While the suspect variation identified so far only explains only about 3.5 percent of the risk for schizophrenia, these results warrant exploring whether using such data to calculate an individual’s risk for developing the disorder might someday be useful in screening for preventive interventions,” explained Thomas R. Insel, M.D., director of the NIH’s National Institute of Mental Health, one funder of the study. “Even based on these early predictors, people who score in the top 10 percent of risk may be up to 20-fold more prone to developing schizophrenia.”
The newfound genomic signals are not simply random sites of variation, say the researchers. They converge around pathways underlying the workings of processes involved in the disorder, such as communication between brain cells, learning and memory, cellular ion channels, immune function and a key medication target.
The Schizophrenia Working Group of the Psychiatric Genomic Consortium (PGC) reports on its genome-wide analysis of nearly 37,000 cases and more than 113,000 controls in the journal Nature, July 21, 2014. The NIMH-supported PGC represents more than 500 investigators at more than 80 research institutions in 25 countries.
Prior to the new study, schizophrenia genome-wide studies had identified only about 30 common gene variants associated with the disorder. Sample sizes in these studies were individually too small to detect many of the subtle effects on risk exerted by such widely shared versions of genes. The PGC investigators sought to maximize statistical power by re-analyzing not just published results, but all available raw data, published and unpublished. Their findings of 108 illness-associated genomic locations were winnowed from an initial pool of about 9.5 million variants.
A comparison of the combined study data with findings in an independent sample of cases and controls suggest that considerably more such associations of this type are likely to be uncovered with larger sample sizes, say the researchers.
There was an association confirmed with variation in the gene that codes for a receptor for the brain chemical messenger dopamine, which is known to be the target for antipsychotic medications used to treat schizophrenia. Yet evidence from the study supports the view that most variants associated with schizophrenia appear to exert their effects via the turning on and off of genes rather than through coding for proteins.
The study found a notable overlap between protein-related functions of some linked common variants and rare variants associated with schizophrenia in other studies. These included genes involved in communication between neurons via the chemical messenger glutamate, learning and memory, and the machinery controlling the influx of calcium into cells.
“The overlap strongly suggests that common and rare variant studies are complementary rather than antagonistic, and that mechanistic studies driven by rare genetic variation will be informative for schizophrenia,” say the researchers.
Among the strongest associations detected, as in in previous genome-wide genetic studies, was for variation in tissues involved in immune system function. Although the significance of this connection for the illness process remains a mystery, epidemiologic evidence has long hinted at possible immune system involvement in schizophrenia.
Findings confirm that it’s possible to develop risk profile scores based on schizophrenia-associated variants that may be useful in research – but for now aren’t ready to be used clinically as a predictive test, say the researchers.
They also note that the associated variations detected in the study may not themselves be the source of risk for schizophrenia. Rather, they may be signals indicating the presence of disease-causing variation nearby in a chromosomal region.
Researchers are following up with studies designed to pinpoint the specific sequences and genes that confer risk. The PGC is also typing genes in hundreds of thousands of people worldwide to enlarge the sample size, in hopes of detecting more genetic variation associated with mental disorders. Successful integration of data from several GWAS studies suggests that this approach would likely be transferrable to similar studies of other disorders, say the researchers.
“These results underscore that genetic programming affects the brain in tiny, incremental ways that can increase the risk for developing schizophrenia,” said Thomas Lehner, Ph.D., chief of NIMH’s Genomics Research Branch. “They also validate the strategy of examining both common and rare variation to understand this complex disorder.”
Beneath the Surface: What Zebrafish Can Tell Us About Anxiety
The right tool for the job is important. A surgeon wouldn’t use a chainsaw when a scalpel offers more control. But sometimes the best treatments available aren’t precise. For example, anxiety medications available today are too blunt in how they target the brain, according to Ian Woods, assistant professor of biochemistry at Ithaca College.
“If you look at current treatments for anxiety disorders, the approach is a bit like taking a sledgehammer to a mosquito,” he said. “The treatments may work for anxiety, but they can have a lot of side effects.”
Woods researches how genetics influence responses to stimuli that can trigger anxiety, and he’s using zebrafish — a tropical member of the minnow family named for the black stripes on their bodies — to do so. He and his team of student researchers examine how fish with tweaked genes respond to different triggers compared to unmodified fish. The work could someday lead to better, more nuanced medications for anxiety disorders.
Zebrafish make ideal test subjects for several reasons. The embryos are transparent and develop outside the mother’s body, making it easy for Woods and his team to observe their growth under a microscope. They develop rapidly, are easy to care for and easy to breed in large quantities.
Specifically, Woods is looking at neuropeptides, which are the chemical messengers between brain cells. Different neuropeptides deliver different messages, which in turn produce different behaviors.
“Fish have the same neuropeptides as humans, and they mostly do the same things in the brain,” Woods said. “We can never faithfully model a complex human behavior like anxiety, but when we’re trying to figure out how the brain works, it’s useful to see inside a fish.”
Woods and his team isolate specific genes to disrupt, amplify, alter or replace, then analyze the movements of the modified fish with the aid of a computerized camera system. They examine responses to stimuli such as slight changes in water temperature, decreases in light intensity, or mild chemical irritants such as mustard oil.
“By observing the ensuing behavioral changes in the fish, we know how that replaced gene changed the message in the brain,” Woods explained. For example, fish exhibiting anxiety-like behaviors might hug the walls of the tank, while the rest will swim toward the middle. It’s not unlike social experiments in which the room temperature is raised gradually to see how human occupants will react.
“Genes typically don’t cause the anxiety,” Woods said. “But they can make organisms more susceptible to environmental triggers that might elicit what we’d call an anxious behavior.”
Anxiety disorders are the most common mental illness in the United States; over 40 million Americans suffer from some type in their lifetimes. But medications can be overprescribed and abused. For example, emergency room visits related to the use of Xanax and related drugs doubled from 2005 to 2011, according to the U.S. Substance Abuse and Mental Health Services Administration.
Schizophrenia and cannabis use may share common genes
Genes that increase the risk of developing schizophrenia may also increase the likelihood of using cannabis, according to a new study led by King’s College London, published today in Molecular Psychiatry.
Previous studies have identified a link between cannabis use and schizophrenia, but it has remained unclear whether this association is due to cannabis directly increasing the risk of the disorder.
The new results suggest that part of this association is due to common genes, but do not rule out a causal relationship between cannabis use and schizophrenia risk.
The study is a collaboration between King’s and the Queensland Institute of Medical Research in Australia, partly funded by the UK Medical Research Council (MRC).
Mr Robert Power, lead author from the MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre at the Institute of Psychiatry at King’s, says: “Studies have consistently shown a link between cannabis use and schizophrenia. We wanted to explore whether this is because of a direct cause and effect, or whether there may be shared genes which predispose individuals to both cannabis use and schizophrenia.”
Cannabis is the most widely used illicit drug in the world, and its use is higher amongst people with schizophrenia than in the general population. Schizophrenia affects approximately 1 in 100 people and people who use cannabis are about twice as likely to develop the disorder. The most common symptoms of schizophrenia are delusions (false beliefs) and auditory hallucinations (hearing voices). Whilst the exact cause is unknown, a combination of physical, genetic, psychological and environmental factors can make people more likely to develop the disorder.
Previous studies have identified a number of genetic risk variants associated with schizophrenia, each of these slightly increasing an individual’s risk of developing the disorder.
The new study included 2,082 healthy individuals of whom 1,011 had used cannabis. Each individual’s ‘genetic risk profile’ was measured – that is, the number of genes related to schizophrenia each individual carried.
The researchers found that people genetically pre-disposed to schizophrenia were more likely to use cannabis, and use it in greater quantities than those who did not possess schizophrenia risk genes.
Power says: “We know that cannabis increases the risk of schizophrenia. Our study certainly does not rule this out, but it suggests that there is likely to be an association in the other direction as well – that a pre-disposition to schizophrenia also increases your likelihood of cannabis use.”
“Our study highlights the complex interactions between genes and environments when we talk about cannabis as a risk factor for schizophrenia. Certain environmental risks, such as cannabis use, may be more likely given an individual’s innate behaviour and personality, itself influenced by their genetic make-up. This is an important finding to consider when calculating the economic and health impact of cannabis.”
(Source: kcl.ac.uk)
Cancer by remote-control: Overlooked DNA shuffling drives deadly paediatric brain tumour
One of the deadliest forms of paediatric brain tumour, Group 3 medulloblastoma, is linked to a variety of large-scale DNA rearrangements which all have the same overall effect on specific genes located on different chromosomes. The finding, by scientists at the European Molecular Biology Laboratory (EMBL), the German Cancer Research Centre (DKFZ), both in Heidelberg, Germany, and Sanford-Burnham Medical Research Institute in San Diego, USA, is published online today in Nature.
To date, the only gene known to play an important role in Group 3 medulloblastoma was a gene called MYC, but that gene alone couldn’t explain some of the unique characteristics of this particular type of medulloblastoma, which has a higher metastasis rate and overall poorer prognosis than other types of this childhood brain tumour. To tackle the question, Jan Korbel’s group at EMBL and collaborators at DKFZ tried to identify new genes involved, taking advantage of the large number of medulloblastoma genome sequences now known.
“We were surprised to see that in addition to MYC there are two other major drivers of Group 3 medulloblastoma – two sister genes called GFI1B and GFI1,” says Korbel. “Our findings could be relevant for research on other cancers, as we discovered that those genes had been activated in a way that cancer researchers don’t usually look for in solid tumours.”
Rather than take the usual approach of looking for changes in individual genes, the team focused on large-scale rearrangements of the stretches of DNA that lie between genes. They found that the DNA of different patients showed evidence of different rearrangements: duplications, deletions, inversions, and even complex alterations involving many ‘DNA-shuffling’ events. This wide array of genetic changes had one effect in common: they placed GFI1B close to highly active enhancers – stretches of DNA that can dramatically increase gene activity. So large-scale DNA changes relocate GFI1B, activating this gene in cells where it would normally be switched off. And that, the researchers surmise, is what drives the tumour to form.
“Nobody has seen such a process in solid cancers before,” says Paul Northcott from DKFZ, “although it shares similarities with a phenomenon implicated in leukaemias, which has been known since the 80s.”
GFI1B wasn’t affected in all cases studied, but in many patients where it wasn’t, a related gene with a similar role, GFI1, was. GFI1B and GFI1 sit on different chromosomes, and interestingly, the DNA rearrangements affecting GFI1 put it next to enhancers sitting on yet other chromosomes. But the overall result was identical: the gene was activated, and appeared to drive tumour formation.
To confirm the role of GFI1B and GFI1 in causing medulloblastoma, the Heidelberg researchers turned to the expertise of Robert Wechsler-Reya’s group at Sanford-Burnham. Wechsler-Reya’s lab genetically modified neural stem cells to have either GFI1B or GFI1 turned on, together with MYC. When they inserted those modified cells into the brains of healthy mice, the rodents developed aggressive, metastasising brain tumours that closely resemble Group 3 medulloblastoma in humans.
These mice are the first to truly mimic the genetics of the human version of Group 3 medulloblastoma, and researchers can now use them to probe further. The mice could, for instance, be used to test potential treatments suggested by these findings. One interesting option to explore, the scientists say, is that highly active enhancers – like the ones they found were involved in this tumour – can be vulnerable to an existing class of drugs called bromodomain inhibitors. And, since neither GFI1B nor GFI1 is normally active in the brain, the study points to possible routes for diagnosing this brain tumour, too.
But the mice also raised another question the scientists are still untangling. For the rodents to develop medulloblastoma-like tumours, activating GFI1 or GFI1B was not enough; MYC also had to be switched on. In human patients, however, scientists have found a statistical link between MYC and GFI1, but not between MYC and GFI1B, so the team is now following up on this partial surprise.
“What we’re learning from this study is that clearly one has to think outside the box when trying to understand cancer genomes,” Korbel concludes.
(Source: embl.de)
A new twist on neurological disease: U-M discovery could aid patients with dystonia, Parkinson’s & more
Twist and hold your neck to the left. Now down, and over to the right, until it hurts. Now imagine your neck – or arms or legs – randomly doing that on their own, without you controlling it.
That’s a taste of what children and adults with a neurological condition called dystonia live with every day – uncontrollable twisting and stiffening of neck and limb muscles.
The mystery of why this happens, and what can prevent or treat it, has long puzzled doctors, who have struggled to help their suffering dystonia patients. Now, new research from a University of Michigan Medical School team may finally open the door to answering those questions and developing new options for patients.
In a new paper in the Journal of Clinical Investigation, the researchers describe new strains of mice they’ve developed that almost perfectly mimic a human form of the disease. They also detail new discoveries about the basic biology of dystonia, made from studying the mice.
They’ll soon make the mice available for researchers everywhere to study, to accelerate understanding of all forms of dystonia and the search for better treatments. The lack of such mice has held back research on dystonia for years.
The U-M team’s success in creating a mouse model for the disease came only after 17 years of stubborn, persistent effort – often in the face of setbacks and failure.
Led by U-M neurologist William Dauer, M.D., the team tried to figure out how and why a gene defect leads to an inherited form of dystonia that, intriguingly, doesn’t start until the pre-teen or teen years, after which it progresses for many years but then stops getting worse after the person reaches their mid-20s.
The gene defect responsible, called DYT1, causes brain cells to make a less-active form of a protein called torsinA. But despite more than a decade of effort by Dauer’s team and many others around the world, no one has been able to translate this information into an animal model with dystonia’s characteristic movements.
Using the childhood onset as a clue, Dauer and his team used cutting-edge genetic technology to severely impair torsinA function during early brain development. This novel twist caused the new mice to closely mimic the human disease: they don’t develop dystonia until they reach preteen age in “mouse years,” and their symptoms stop getting worse after a while.
With this powerful tool in hand, Dauer’s team were now able to peer into the brains of these animals to begin to unravel the mysteries of the disease.
In an unexpected development, they found that the lack of torsinA in the brains of dystonic mice led to the death of neurons – a process called neurodegeneration – in just a few highly localized parts of the brain that control movement. Like the dystonic movements, this neurodegeneration began in young mice, progressed for a time, and then became fixed.
“We’ve created a model for understanding why certain parts of the brain are more vulnerable to problems from a certain genetic insult,” says Dauer, an associate professor in the U-M departments of Neurology and Cell & Developmental Biology.
“In this case, we’re showing that in dystonia, the lack of this particular protein during a critical window of time is causing cell death. Every disease is telling us something about biology — one just has to listen carefully.”
(Image caption: The brains of the mice with dystonia (shown in the right column) had much higher levels of neuron death than those without the condition (left column) — and this neurodegeneration was limited to certain areas involved in controlling muscle movements.)
More discoveries to come
Dauer and his team don’t yet know why only one-third of human DYT1 gene mutation carriers develop primary dystonia during their school years, and why those who don’t develop the disease before their early 20s will never go on to develop it.
They believe some critical events during the brain’s development in infancy and childhood may have to do with it - and they’re already working to explore that question in mice.
They also believe their mouse model will help them and other researchers understand how dystonia occurs in people who have Parkinson’s disease, Huntington’s disease, or damage caused by a stroke or brain injury. Some people develop dystonia without either a known gene defect or any of these other diagnoses – a condition called idiopathic dystonia.
In all these cases, as in people with DYT1 mutations, dystonia’s twisting and curling motions likely arise from problems in the area of the brain that controls the body’s motor control system.
In other words, something’s going wrong in the process of sending signals to the nerves that control muscles involved in movement. Studying a “pure” form of dystonia using the mice will allow researchers to understand just what’s going on.
The team’s ultimate goal is to find new treatments for all kinds of dystonia. Currently, children, teens and young adults who develop it can take medications or even opt for a form of neurosurgery called deep brain stimulation. But the drugs carry major side effects and are only partially effective – and brain surgery carries its own risks. Dauer and his team are working to screen drug candidates.
(Source: uofmhealth.org)
Scientists Pinpoint How Genetic Mutation Causes Early Brain Damage
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have shed light on how a specific kind of genetic mutation can cause damage during early brain development that results in lifelong learning and behavioral disabilities. The work suggests new possibilities for therapeutic intervention.
The study, which focuses on the role of a gene known as Syngap1, was published June 18, 2014, online ahead of print by the journal Neuron. In humans, mutations in Syngap1 are known to cause devastating forms of intellectual disability and epilepsy.
“We found a sensitive cell type that is both necessary and sufficient to account for the bulk of the behavioral problems resulting from this mutation,” said TSRI Associate Professor Gavin Rumbaugh, who led the study. “Because we found the root biological cause of this genetic brain disorder, we can now shift our research toward developing tailor-made therapies for people affected by Syngap1 mutations.”
In the study, Rumbaugh and his colleagues used a mouse model to show that mutations in Syngap1 damage the development of a kind of neuron known as glutamatergic neurons in the young forebrain, leading to intellectual disability. Higher cognitive processes, such as language, reasoning and memory arise in children as the forebrain develops.
Repairing damaging Syngap1 mutations in these specific neurons during development prevented cognitive abnormalities, while repairing the gene in other kinds of neurons and in other locations had no effect.
Rumbaugh noted prenatal diagnosis of some infant genetic disorders is on the horizon. Technological advances in genetic sequencing allow for individual genomes to be scanned for damaging mutations; it is possible to scan the entire genome of a child still in the womb. “Our research suggests that if Syngap1 function can be fixed very early in development, this should protect the brain from damage and permanently improve cognitive function,” said TSRI Research Associate Emin Ozkan, a first author of the study, along with TSRI Research Associate Thomas Creson. “In theory, patients then wouldn’t have to be subjected to a lifetime of therapies and worry that the drugs might stop working or have side effects from chronic use.”
Mutations to Syngap1 are a leading cause of “sporadic intellectual disability,” resulting from new, random mutations arising spontaneously in genes, rather than faulty genes inherited from parents. Intellectual disability affects approximately one to three percent of the population worldwide.
Rumbaugh and his colleagues are continuing to investigate. “Our findings have also identified exciting potential biomarkers in the brain of cognitive failure, allowing us to test new therapeutic strategies in our Syngap1 animal model,” said Creson.
(Source: newswise.com)
International study yields important clues to the genetics of epilepsy
An international team of researchers has discovered a significant genetic component of Idiopathic Generalized Epilepsy (IGE), the most common form of epilepsy. Epilepsy is a neurological disorder characterized by sudden, uncontrolled electrical discharges in the brain expressed as a seizure. The new research, published in this week’s issue of EMBO Reports, implicates a mutation in the gene for a protein, known as cotransporter KCC2.
KCC2 maintains the correct levels of chloride ions in neurons, playing a major part in regulating excitation and inhibition of neurons. The results indicate that a genetic mutation of KCC2 might be a risk factor for developing IGE.
“We found a clear statistical association between two variants of KCC2 and severe IGE in a large French-Canadian patient sample,” said Dr. Guy Rouleau, Director of the Montreal Neurological Institute and Hospital (The Neuro) at McGill University and the McGill University Health Centre, and senior author of the study. “Our data not only corroborate recent findings by other groups but vastly extend them from genetic, physiological and biochemical standpoints.” The first authors on the paper are Dr. Kristopher Kahle, chief neurosurgery resident at Massachusetts General Hospital and post-doctoral fellow at Harvard University, and Dr. Nancy Merner, a former post-doctoral fellow in Dr. Rouleau’s laboratory and now a professor at Auburn University.
The study examined 380 French Canadians with IGE living in Montreal and Quebec City. Results were compared to data from a control group of more than 1,200 people. “KCC2 is a hot topic in neuroscience given its important role in neuronal signaling and in its potential role in neurological diseases such as epilepsy, neuropathic pain, and other diseases,” said Dr. Rouleau.
Each day in Canada, an average of 42 people learn that they have epilepsy. In 50 – 60% of cases, the cause of epilepsy is unknown. The major form of treatment is long-term drug therapy. Drugs are not a cure and can have numerous, sometimes severe, side effects. Brain surgery is recommended only when medication fails and when the seizures are confined to one area of the brain where brain tissue can be safely removed without damaging personality or function.
(Source: publications.mcgill.ca)
Gene mutation discovery could explain brain disorders in children
Researchers have discovered that mutations in one of the brain’s key genes could be responsible for impaired mental function in children born with an intellectual disability.
The research, published today in the journal, Human Molecular Genetics, proves that the gene, TUBB5, is essential for a healthy functioning brain.
It’s estimated that intellectual disability affects up to four per cent of people worldwide, and two per cent of all Australians. One of the ways in which intellectual disability occurs is through genetic mutations, which cause problems with normal fetal brain development.
During fetal brain development, TUBB5 is essential for the proper placement and wiring of new neurons. When the gene is mutated, the brain, which sends and receives messages to the rest of the body, is impaired.
Lead researcher, Dr Julian Heng, from the Australian Regenerative Medicine Institute (ARMI) at Monash University, said genetic mutations to TUBB5 could be responsible for a range of intellectual disabilities. It could also affect the development of basic motor skills such as walking.
“TUBB5 works like a type of scaffolding inside neurons, enabling them to shape their connections to other neurons, so it’s essential for healthy brain development. If the scaffolding is faulty, in this case if TUBB5 mutates, it can have serious consequences,” Dr Heng said.
These new findings build on the team’s collaborative work with researchers in Austria, which led to the discovery of TUBB5 mutations in human brain disorders in 2012. By looking at just three unrelated patients with microcephaly, a rare brain disease in children, the team found striking similarities – each had a mutation to TUBB5. The team also provided the first evidence that the TUBB5 mutations were responsible for each patient’s disorder.
Dr Heng said the research could have important implications, not only for intellectual disabilities but also for a wide range of developmental disorders.
“Learning more about the TUBB5 gene and its mutations could reveal how it shapes the connections of neurons in normal and diseased brain states.
“We’re just at the beginning of this work but if we can understand why and how mutations occur to TUBB5, we may even be able to repair these mutations. In the future, we believe this work will enable us to develop new therapies to transform people’s lives,” Dr Heng said.
The work may potentially lead to new information about the causes and possible treatments for other brain developmental syndromes, including autism, a condition that affects as many as 1 in 160 children.
Dr Heng said that because TUBB5 belongs to a family of genes which produce the scaffolding in neurons, it means that there is scope for further study into its impact.
“By learning what these scaffolding proteins do to help neurons make brain circuits, we might be able to pinpoint the underlying causes of a wide range of brain disorders in children, and develop more targeted treatments,” Dr Heng said.
Scientists believe that in the future this knowledge, combined with regenerative medicine techniques, could also aid the replacement of neurons in times of brain injury or disease.
The next phase of the research will be to develop a working model to better understand how TUBB5 can be targeted for gene therapy.