Posts tagged gene mutation
Articles and news from the latest research reports.
New lead for potential Parkinson’s treatment: Effects of high-risk Parkinson’s mutation are reversible
Mutations in a gene called LRRK2 carry a well-established risk for Parkinson’s disease, however the basis for this link is unclear.
(Image caption: A microscope image of a cultured cell)
The team, led by Parkinson’s UK funded researchers Dr Kurt De Vos from the Department of Neuroscience and Dr Alex Whitworth from the Department of Biomedical Sciences, found that certain drugs could fully restore movement problems observed in fruit flies carrying the LRRK2 Roc-COR Parkinson’s mutation.
These drugs, deacetylase inhibitors, target the transport system and reverse the defects caused by the faulty LRRK2 within nerve cells. The study is published in Nature Communications.
Dr De Vos, a Lecturer in Translational Neuroscience at the world-leading Sheffield Institute for Translational Neuroscience (SITraN), said: “Our study provides compelling evidence that there is a direct link between defective transport within nerve cells and movement problems caused by the LRRK2 Parkinson’s mutation in flies.”
Co-investigator Dr Alex Whitworth explained: “We could also show that these neuronal transport defects caused by the LRRK2 mutation are reversible.
“By targeting the transport system with drugs, we could not only prevent movement problems, but also fully restore movement abilities in fruit flies who already showed impaired movement marked by a significant decrease in both climbing and flight ability.”
The LRRK2 gene produces a protein that affects many processes in the cell. It is known to bind to the microtubules, the cells’ transport tracks. A defect in this transport system has been suggested to contribute to Parkinson’s disease. The researchers have investigated this link and have now found the evidence that certain LRRK2 mutations affect transport in nerve cells which leads to movement problems observed in the fruit fly (Drosophila).
The team then used several approaches to show that preventing the association of the mutant LRRK2 protein with the microtubule transport system rescues the transport defects in nerve cells, as well as the movement deficits in fruit flies.
Dr De Vos added: “We successfully used drugs called deacetylase inhibitors to increase the acetylated form of α-tubulin within microtubules which does not associate with the mutant LRRK2 protein. We found that increasing microtubule acetylation had a direct impact on cellular axonal transport.
“These are very promising results which point to a potential Parkinson’s therapy. However, further studies are needed to confirm that this rescue effect also applies in humans.“
Dr Beckie Port, Research Communications Officer at Parkinson’s UK, which helped to fund the study, said: “This research gives hope that, for people with a particular mutation in their genes, it may one day be possible to intervene and stop the progression of Parkinson’s.
“The study has only been carried out in fruit flies, so much more research is needed before we know if these findings could lead to new treatment approaches for people with Parkinson’s.”
(Source: sheffield.ac.uk)
Scientists Shed Light on Cause of Spastic Paraplegia
Scientists at The Scripps Research Institute (TSRI) have discovered that a gene mutation linked to hereditary spastic paraplegia, a disabling neurological disorder, interferes with the normal breakdown of triglyceride fat molecules in the brain. The TSRI researchers found large droplets of triglycerides within the neurons of mice modeling the disease.
The findings, reported this week online ahead of print by the journal Proceedings of the National Academy of Sciences, point the way to potential therapies and showcase an investigative strategy that should be useful in determining the biochemical causes of other genetic illnesses. Scientists in recent decades have linked thousands of gene mutations to human diseases, yet many of the genes in question code for proteins of unknown function.
“We often need to understand the protein function that is disrupted by a gene mutation, if we’re going to understand the mechanistic basis for the disease and move towards developing a therapy, and that is what we’ve tried to do here,” said Benjamin F. Cravatt, professor and chair of TSRI’s Department of Chemical Physiology.
There is currently no treatment for hereditary spastic paraplegia (HSP), a set of genetic illnesses whose symptoms include muscle weakness and stiffness, and in some cases cognitive impairments. About 100,000 people worldwide live with HSP.
Uncovering Clues
In the new study, Cravatt and members of his laboratory, including graduate student Jordon Inloes and postdoctoral fellow Ku-Lung Hsu, focused on DDHD2, an enzyme of unclear function whose gene is mutated in a subset of HSP cases. “These cases involving DDHD2 disruption feature cognitive defects as well as spasticity and muscle wasting, so they’re among the more devastating forms of this illness,” said Cravatt.
To start, the researchers created a mouse model of DDHD2-related HSP, in which a targeted deletion from the DDHD2 gene eliminated the expression of the DDHD2 protein. “These mice showed symptoms similar to those of HSP patients, including abnormal gait and lower performance on tests of movement and cognition,” said Inloes.
Prior research had suggested that the DDHD2 enzyme is expressed in the brain and is involved somehow in lipid metabolism. One study reported elevated levels of an unknown fat molecule in the brains of DDHD2-mutant HSP patients. Cravatt’s team compared the tissues of the no-DDHD2 mice to the tissues of mice with normal versions of the gene, and also found that the mutant mice had much higher levels of a type of fat molecule, principally in the brain.
Using a set of sophisticated “lipidomics” tests to analyze the accumulating fat molecules, they identified them as triglycerides—a major component of stored fat in the body, and a risk factor for obesity, atherosclerosis and type 2 diabetes.
“We were able to show as well, using both light microscopy and electron microscopy, that droplets of triglyceride-rich fat are present in the neurons of DDHD2-knockout mice, in several brain regions, but are not present in normal mice,” said Inloes.
For the next phase of the study, Cravatt’s team developed a complementary tool for studying DDHD2’s function: a specific inhibitor of the DDHD2 enzyme, one of a set of powerful enzyme-blocking compounds they had identified in a study reported last year. “After four days of treatment with this inhibitor, normal mice showed an increase in brain triglycerides,” said Inloes. “This suggests that DDHD2 normally breaks down triglycerides, and its inactivity allows triglycerides to build up.”
Finally the team confirmed DDHD2’s role in triglyceride metabolism by showing that triglycerides are rapidly broken down into smaller fatty acids in its presence.
“These findings give us some insight, at least, into the biochemical basis of the HSP syndrome,” said Cravatt.
Looking Ahead
Future projects in this line of inquiry, he adds, include a study of how triglyceride droplets in neurons lead to impairments of movement and cognition, and research on potential therapies to counter these effects, including the possible use of diacylglycerol transferase (DGAT) inhibitors, which reduce the natural production of triglycerides.
Cravatt also notes that the same approach used in this study can be applied to other enzymes in DDHD2’s class (serine hydrolases), whose dysfunctions cause human neurological disorders.
(Source: scripps.edu)
Scientists Develop First Animal Model for ALS Dementia
The first animal model for ALS dementia, a form of ALS that also damages the brain, has been developed by Northwestern Medicine scientists. The advance will allow researchers to directly see the brains of living mice, under anesthesia, at the microscopic level. This will allow direct monitoring of test drugs to determine if they work.
This is one of the latest research findings since the ALS Ice Bucket Challenge heightened interest in the disease and the need for expanded research and funding.
“This new model will allow rapid testing and direct monitoring of drugs in real time,” said Northwestern scientist and study senior author Teepu Siddique, MD. “This will allow scientists to move quickly and accelerate the testing of drug therapies.”
The new mouse model has the pathological hallmarks of the disease in humans with mutations in the genes for UBQLN2 (ubliqulin 2) and SQSTM1 (P62) that Siddique and colleagues identified in 2011. That pathology was linked to all forms of ALS and ALS/dementia.
Dr. Siddique and Han-Xiang Deng, MD, the corresponding authors on the paper, said they have reproduced behavioral, neurophysiological and pathological changes in a mouse that mimic this form of dementia associated with ALS (amyotrophic lateral sclerosis).
Dr. Siddique is the Les Turner ALS Foundation/Herbert C. Wenske Professor of Neurology at Northwestern University Feinberg School of Medicine and a neurologist at Northwestern Memorial Hospital. Dr. Deng is a research professor in Neurology at Feinberg.
The study was published Sept. 22 in the Proceedings of the National Academy of Sciences.
It’s been difficult for scientists to reproduce the genetic mutations of ALS, especially ALS/dementia in animal models, Dr. Siddique noted, which has hampered drug therapy testing.
Five percent or more of ALS cases, also known as Lou Gherig’s disease, also have ALS/dementia.
“ALS with dementia is an even more vicious disease than ALS alone because it attacks the brain causing changes in behavior and language well as causing paralysis,” Dr. Siddique said.
ALS affects an estimated 350,000 people worldwide, with an average survival of three years. In this progressive neurological disorder, the degeneration of neurons leads to muscle weakness and impaired speaking, swallowing and breathing, eventually causing paralysis and death. The associated dementia affects behavior and may affect decision-making, judgment, insight and language.
(Source: feinberg.northwestern.edu)
Researcher Develops and Proves Effectiveness of New Drug for Spinal Muscular Atrophy
According to recent studies, approximately one out of every 40 individuals in the United States is a carrier of the gene responsible for spinal muscular atrophy (SMA), a neurodegenerative disease that causes muscles to weaken over time. Now, researchers at the University of Missouri have made a recent breakthrough with the development of a new compound found to be highly effective in animal models of the disease. In April, a patent was filed for the compound for use in SMA.
“The strategy our lab is using to fight SMA is to ‘repress the repressor,’” said Chris Lorson, a researcher in the Bond Life Sciences Center and professor in the MU Department of Veterinary Pathobiology. “It’s a lot like reading a book, but in this case, the final chapter of the book—or the final exon of the genetic sequence—is omitted. The exciting part is that the important chapter is still there—and can be tricked into being read correctly, if you know how. The new SMA therapeutic compound, an antisense oligonucleotide, repairs expression of the gene affected by the disease.”
In individuals affected by SMA, the spinal motor neuron-1 (SMN1) gene is mutated and lacks the ability to process a key protein that helps muscle neurons function. Muscles in the lower extremities are usually affected first, followed by muscles in the upper extremities, including areas around the neck and spine.
Fortunately, humans have a nearly identical copy gene called SMN2. Lorson’s drug targets that specific genetic sequence and allows proper “editing” of the SMN2 gene. The drug allows the SMN2 gene to bypass the defective gene and process the protein that helps the muscle neurons function.
Lorson’s breakthrough therapeutic compound was patented in April. His research found that the earlier the treatment can be administered in mice with SMA, the better the outcome. In mice studies, the drug improved the survival rate by 500 to 700 percent, with a 90 percent improvement demonstrated in severe SMA cases, according to the study.
Although there is no cure for SMA currently, the National Institutes of Health (NIH) has listed SMA as the neurological disease closest to finding a cure, due in part to effective drugs like the one developed in Lorson’s lab.
Neuroscientists identify key role of language gene
Neuroscientists have found that a gene mutation that arose more than half a million years ago may be key to humans’ unique ability to produce and understand speech.
Researchers from MIT and several European universities have shown that the human version of a gene called Foxp2 makes it easier to transform new experiences into routine procedures. When they engineered mice to express humanized Foxp2, the mice learned to run a maze much more quickly than normal mice.
The findings suggest that Foxp2 may help humans with a key component of learning language — transforming experiences, such as hearing the word “glass” when we are shown a glass of water, into a nearly automatic association of that word with objects that look and function like glasses, says Ann Graybiel, an MIT Institute Professor, member of MIT’s McGovern Institute for Brain Research, and a senior author of the study.
“This really is an important brick in the wall saying that the form of the gene that allowed us to speak may have something to do with a special kind of learning, which takes us from having to make conscious associations in order to act to a nearly automatic-pilot way of acting based on the cues around us,” Graybiel says.
Wolfgang Enard, a professor of anthropology and human genetics at Ludwig-Maximilians University in Germany, is also a senior author of the study, which appears in the Proceedings of the National Academy of Sciences this week. The paper’s lead authors are Christiane Schreiweis, a former visiting graduate student at MIT, and Ulrich Bornschein of the Max Planck Institute for Evolutionary Anthropology in Germany.
All animal species communicate with each other, but humans have a unique ability to generate and comprehend language. Foxp2 is one of several genes that scientists believe may have contributed to the development of these linguistic skills. The gene was first identified in a group of family members who had severe difficulties in speaking and understanding speech, and who were found to carry a mutated version of the Foxp2 gene.
In 2009, Svante Pääbo, director of the Max Planck Institute for Evolutionary Anthropology, and his team engineered mice to express the human form of the Foxp2 gene, which encodes a protein that differs from the mouse version by only two amino acids. His team found that these mice had longer dendrites — the slender extensions that neurons use to communicate with each other — in the striatum, a part of the brain implicated in habit formation. They were also better at forming new synapses, or connections between neurons.
Pääbo, who is also an author of the new PNAS paper, and Enard enlisted Graybiel, an expert in the striatum, to help study the behavioral effects of replacing Foxp2. They found that the mice with humanized Foxp2 were better at learning to run a T-shaped maze, in which the mice must decide whether to turn left or right at a T-shaped junction, based on the texture of the maze floor, to earn a food reward.
The first phase of this type of learning requires using declarative memory, or memory for events and places. Over time, these memory cues become embedded as habits and are encoded through procedural memory — the type of memory necessary for routine tasks, such as driving to work every day or hitting a tennis forehand after thousands of practice strokes.
Using another type of maze called a cross-maze, Schreiweis and her MIT colleagues were able to test the mice’s ability in each of type of memory alone, as well as the interaction of the two types. They found that the mice with humanized Foxp2 performed the same as normal mice when just one type of memory was needed, but their performance was superior when the learning task required them to convert declarative memories into habitual routines. The key finding was therefore that the humanized Foxp2 gene makes it easier to turn mindful actions into behavioral routines.
The protein produced by Foxp2 is a transcription factor, meaning that it turns other genes on and off. In this study, the researchers found that Foxp2 appears to turn on genes involved in the regulation of synaptic connections between neurons. They also found enhanced dopamine activity in a part of the striatum that is involved in forming procedures. In addition, the neurons of some striatal regions could be turned off for longer periods in response to prolonged activation — a phenomenon known as long-term depression, which is necessary for learning new tasks and forming memories.
Together, these changes help to “tune” the brain differently to adapt it to speech and language acquisition, the researchers believe. They are now further investigating how Foxp2 may interact with other genes to produce its effects on learning and language.
This study “provides new ways to think about the evolution of Foxp2 function in the brain,” says Genevieve Konopka, an assistant professor of neuroscience at the University of Texas Southwestern Medical Center who was not involved in the research. “It suggests that human Foxp2 facilitates learning that has been conducive for the emergence of speech and language in humans. The observed differences in dopamine levels and long-term depression in a region-specific manner are also striking and begin to provide mechanistic details of how the molecular evolution of one gene might lead to alterations in behavior.”
Researchers Identify New Rare Neuromuscular Disease
An international team of researchers has identified a new inherited neuromuscular disorder. The rare condition is the result of a genetic mutation that interferes with the communication between nerves and muscles, resulting in impaired muscle control.
The new disease was diagnosed in two families – one in the U.S. and the other in Great Britain – and afflicts multiple generations. The discovery was published in the American Journal of Human Genetics.
“This discovery gives us new insight into the mechanisms of diseases that are caused by a breakdown in neuromuscular signal transmission,” said David Herrmann, M.B.B.Ch., a professor in the Department of Neurology at the University of Rochester School of Medicine and Dentistry and co-lead author of the study. “It is our hope that these findings will help identify new targets for therapies that can eventually be used to treat these diseases.”
The focus of the research is the neuromuscular junction, the point at which the axon fibers that extend from peripheral nerves meet the muscle cells. The chemical signals that pass across the junction are essential for motor function.
There are a number of disorders – both acquired and inherited – that interfere with the communication that occurs at the neuromuscular junction. For example, in Lambert-Eaton myasthenic syndrome, which is most commonly triggered by certain cancers, the body’s own immune system attacks the neuromuscular junction, interrupting signal transmission. These diseases, which are rare, result in muscle weakness and fatigue, primarily in the limbs.
While the families in the study had at one point been diagnosed with other neuromuscular conditions, the researchers identified them as unique, due to their particular motor abnormalities, including problems resembling Lambert-Eaton, and because the disease was passed from one generation to the next.
The researchers compiled a genetic profile of the family members. Specifically, they analyzed the section of DNA code responsible for creating proteins using a technique called whole exome sequencing.
They discovered that the two different families had mutations in the code that creates the protein synaptotagmin 2 (SYT2). Scientists have long understood the function of this protein, but it had never before been associated with a disease in humans.
SYT2 is present at the pre-synaptic terminal, the end of the nerve cell that sits at the neuromuscular junction and helps the cells sense fluctuations in calcium levels. Calcium plays an important role in the electrical function of cells and, in the case of the neuromuscular junction, helps dictate the release of acetylcholine, a chemical responsible for passing communication between the nerve and muscle cells.
In the two families, the mutation disrupted the ability of the nerve cells to sense the changes in calcium levels that would normally trigger the release of acetylcholine. As a result, communication was disrupted and muscle control was impaired.
The authors have used the mutation in SYT2 to create a fruit fly (drosophila) model of the disease. Fruit flies are an important research tool and the study of their neurobiology has contributed greatly to our understanding of neurological development and diseases and the researchers see this as a first step to the development of potential new therapies to treat the condition.
(Source: urmc.rochester.edu)
Study Links Autistic Behaviors to Enzyme
Fragile X syndrome (FXS) is a genetic disorder that causes obsessive-compulsive and repetitive behaviors, and other behaviors on the autistic spectrum, as well as cognitive deficits. It is the most common inherited cause of mental impairment and the most common cause of autism.
Now biomedical scientists at the University of California, Riverside have published a study that sheds light on the cause of autistic behaviors in FXS. Appearing online today (July 23) in the Journal of Neuroscience, and highlighted also on the cover in this week’s print issue of the journal, the study describes how MMP-9, an enzyme, plays a critical role in the development of autistic behaviors and synapse irregularities, with potential implications for other autistic spectrum disorders.
MMP-9 is produced by brain cells. Inactive, it is secreted into the spaces between cells of the brain, where it awaits activation. Normal brains have quite a bit of inactive MMP-9, and the activation of small amounts has significant effects on the connections between neurons, called synapses. Too much MMP-9 activity causes synapses in the brain to become unstable, leading to functional deficits.
“Our study targets MMP-9 as a potential therapeutic target in Fragile X and shows that genetic deletion of MMP-9 favorably impacts key aspects of FXS-associated anatomical alterations and behaviors in a mouse model of Fragile X,” said Iryna Ethell, a professor of biomedical sciences in the UC Riverside School of Medicine, who co-led the study. “We found that too much MMP-9 activity causes synapses to become unstable, which leads to functional deficits that depend on where in the brain that occurs.”
Ethell explained that mutations in FMR1, a gene, have been known for more than a decade to cause FXS, but until now it has been unclear how these mutations cause unstable synapses and characteristic physical features of this disorder. The new findings expand on earlier work by the research group that showed that an MMP-9 inhibitor, minocycline, can reduce behavioral aspects of FXS, which then led to its use to treat FXS.
To further establish a causative role for MMP-9 in the development of FXS-associated features, including autistic behaviors, the authors generated mice that were missing both FMR1 and MMP-9. They found that while mice with a single FMR1 mutation showed autistic behaviors and macroorchidism (abnormally large testes), mice that also lacked MMP-9 showed no autistic behaviors.
“Our work points directly to MMP-9 over-activation as a cause for synaptic irregularities in FXS, with potential implications for other autistic spectrum disorders and perhaps Alzheimer’s disease,” said Doug Ethell, the head of Molecular Neurobiology at the Western University of Health Sciences, Pomona, Calif., and a coauthor on the study.
The research paper represents many years of bench work and effort by a dedicated team led by the Ethells. The work was primarily done in mice, but human tissue samples were also analyzed, with findings found to be consistent. Specifically, the work involved assessing behaviors, biochemistry, activity and anatomy of synaptic connections in the brain of a mouse model of FXS, as well as the creation of a new mouse line that lacked both the FXS gene and MMP-9.
FXS affects both males and females, with females often having milder symptoms than males. It is estimated that about 1 in 5,000 males are born with the disorder.
The Ethells were joined in the study by UCR’s Harpreet Sidhu (first author of the research paper), Lorraine E. Dansie, and Peter Hickmott. Sidhu and Dansie are neuroscience graduate students; Hickmott is an associate professor of psychology.
Next, the researchers plan to understand how MMP-9 regulates synapse stability inside the neurons. They also plan to find drugs that specifically target MMP-9 without side effects such as new tetracycline derivatives that are potent inhibitors of MMP-9 but lack antibiotic properties.
“Although minocycline was successfully used in clinical trial in FXS, it has some side effects associated with its antibiotic properties, such gastrointestinal irritation,” Iryna Ethell said. “We, therefore, plan to test new non-antibiotic minocycline derivatives. These compounds lack antibiotic activity but still act as non-competitive inhibitors of MMP-9 similar to minocycline.”
Study finds potential genetic link between epilepsy and neurodegenerative disorders
A recent scientific discovery showed that mutations in prickle genes cause epilepsy, which in humans is a brain disorder characterized by repeated seizures over time. However, the mechanism responsible for generating prickle-associated seizures was unknown.
A new University of Iowa study, published online July 14 in the Proceedings of the National Academy of Sciences, reveals a novel pathway in the pathophysiology of epilepsy. UI researchers have identified the basic cellular mechanism that goes awry in prickle mutant flies, leading to the epilepsy-like seizures.
“This is to our knowledge the first direct genetic evidence demonstrating that mutations in the fly version of a known human epilepsy gene produce seizures through altered vesicle transport,” says John Manak, senior author and associate professor of biology in the College of Liberal Arts and Sciences and pediatrics in the Carver College of Medicine.
Seizure suppression in flies
A neuron has an axon (nerve fiber) that projects from the cell body to different neurons, muscles, and glands. Information is transmitted along the axon to help a neuron function properly.
Manak and his fellow researchers show that seizure-prone prickle mutant flies have behavioral defects (such as uncoordinated gait) and electrophysiological defects (problems in the electrical properties of biological cells) similar to other fly mutants used to study seizures. The researchers also show that altering the balance of two forms of the prickle gene disrupts neural information flow and causes epilepsy.
Further, they demonstrate that reducing either of two motor proteins responsible for directional movement of vesicles (small organelles within a cell that contain biologically important molecules) along tracks of structural proteins in axons can suppress the seizures.
“The reduction of either of two motor proteins, called Kinesins, fully suppressed the seizures in the prickle mutant flies,” says Manak, faculty member in the Interdisciplinary Graduate Programs in Genetics, Molecular and Cellular Biology, and Health Informatics. “We were able to use two independent assays to show that we could suppress the seizures, effectively ‘curing’ the flies of their epileptic behaviors.”
Genetic link between epilepsy and Alzheimer’s
This new epilepsy pathway was previously shown to be involved in neurodegenerative diseases, including Alzheimer’s and Parkinson’s.
Manak and his colleagues note that two Alzheimer’s-associated proteins, amyloid precursor protein and presenilin, are components of the same vesicle, and mutations in the genes encoding these proteins in flies affect vesicle transport in ways that are strikingly similar to how transport is impacted in prickle mutants.
“We are particularly excited because we may have stumbled upon one of the key genetic links between epilepsy and Alzheimer’s, since both disorders are converging on the same pathway,” Manak says. “This is not such a crazy idea. In fact, Dr. Jeff Noebels, a leading epilepsy researcher, has presented compelling evidence suggesting a link between these disorders. Indeed, patients with inherited forms of Alzheimer’s disease also present with epilepsy, and this has been documented in a number of published studies.”
Manak adds, “If this connection is real, then drugs that have been developed to treat neurodegenerative disorders could potentially be screened for anti-seizure properties, and vice versa.”
Manak’s future research will involve treating seizure-prone flies with such drugs to see if he can suppress their seizures.
(Source: now.uiowa.edu)
(Image caption: These scans show atrophy of the cerebellum in a boy with Christianson Syndrome. This symptom was observed in some, but not all boys, with the condition. Credit: Eric Morrow/Brown University)
Diagnostic criteria for Christianson Syndrome
Because the severe autism-like condition Christianson Syndrome was only first reported in 1999 and some symptoms take more than a decade to appear, families and doctors urgently need fundamental information about it. A new study that doubles the number of cases now documented in the scientific literature provides the most definitive characterization of CS to date. The authors therefore propose the first diagnostic criteria for the condition.
"We’re hoping that clinicians will use these criteria and that there will be more awareness among clinicians and the community about Christianson Syndrome," said Brown University biology and psychiatry Assistant Professor Dr. Eric Morrow, senior author of the study in press in the Annals of Neurology. “We’re also hoping this study will impart an opportunity for families to predict what to expect for their child and what’s a part of the syndrome.”
In conducting their study, which includes detailed behavioral, medical and genetic observations of 14 boys with CS from 12 families, the team of scientists and physicians worked closely with families of the small but fast-growing Christianson Syndrome Association , including hosting the group’s inaugural conference at Brown’s Alpert Medical School last summer.
In their study, Morrow’s team was able to quantify the most frequent symptoms specific to CS. These include moderate to severe intellectual disability, epilepsy, difficulty or inability walking and talking, attenuated head and brain growth, and hyperactivity. Boys sometimes exhibit other specific symptoms – including autism-like behaviors, low height and weight, acid reflux, and regressions in speech and motor skills after age 10 – that the researchers include as secondary proposed diagnostic criteria. A third of the boys also had potentially neurodegenerative problems such as atrophy of the cerebellum.
What’s still not clear is whether the disease limits the eventual lifespan of patients.
Distinct genetic cause
Many CS traits, including a very happy disposition, appear similar to those of another autism-like condition, Angelman Syndrome, but the study defines important differences.
Among the most important ones is that the two syndromes have distinct genetic underpinnings. In all CS cases, said Morrow who treats autism patients at the E. P. Bradley Hospital in East Providence, boys have a mutation on the SLC9A6 gene on the X chromosome that disables production of a protein called NHE6 that is important for neurological development.
Girls, who have two X chromosomes, can also be carriers of CS mutations, but they appear to be affected differently and less severely or not at all, the study reports.
The connection to the SLC9A6 gene was first discovered in 2008. In analyzing the genomes of each patient and their parents in the new study, lead authors Matthew Pescosolido, a graduate student, and David Stein, a former undergraduate, found that each boy had only one mutation, but there were many different ones across the entire group. More often than not, they determined, the mutation was not inherited, but an unlucky “de novo” change that occurred in the affected boy. In two situations, boys in unrelated families happened to share the same mutation. These recurrent mutations suggest that there may be hotspots in the DNA for mutation at these sites, Morrow said, although further research will be necessary to sort this out.
Morrow said there is evidence that SLC9A6 mutations – and therefore CS – may be a relatively common source of X-linked intellectual disability. One study, for example found that SLC9A6 mutations in two of 200 people suspected of having X-linked ID. Another found that 1 in 19 families with a case of ID exhibited a mutation that truncated the NHE6 protein.
"If we assume that between 1-3 percent of the world’s population is diagnosed with an intellectual disability and approximately 10-20 percent of the causes are due to X-linked genes, then we can estimate that CS may affect between 1 in 16,000 to 100,000 people," Morrow and his co-authors wrote. Worldwide that frequency would add up to more than 70,000 cases.
Relevance to autism, epilepsy
In a paper published last year, Morrow’s research group found that NHE6 is underexpressed in the brains of many children with more general forms of autism. This potential connection suggests that learning about CS can help doctors and scientists learn about autism.
Similarly by studying the regression of walking and verbal skills among Christianson boys, Morrow said researchers could learn more about regressions in autism.
"Christianson syndrome, I hope will be a model," Morrow said. "If we could understand the biological mechanism that leads to that loss, and we can prevent it, by developing a treatment, then these kids will remain further ahead."
Such advances will require much more study, but Morrow said that by uncovering a variety of mutations that all lead to the disease, the study provides a wealth of new information for that work.
"We can now study these different mutations and learn how this protein works by how it gets inactivated," he said. "All the different ways it gets inactivated can actually inform us about the different components of the protein that have an important function."
Fatal cell malfunction ID’d in Huntington’s disease
Researchers believe they have learned how mutations in the gene that causes Huntington’s disease kill brain cells, a finding that could open new opportunities for treating the fatal disorder. Scientists first linked the gene to the inherited disease more than 20 years ago.
Huntington’s disease affects five to seven people out of every 100,000. Symptoms, which typically begin in middle age, include involuntary jerking movements, disrupted coordination and cognitive problems such as dementia. Drugs cannot slow or stop the progressive decline caused by the disorder, which leaves patients unable to walk, talk or eat.
Lead author Hiroko Yano, PhD, of Washington University School of Medicine in St. Louis, found in mice and in mouse brain cell cultures that the disease impairs the transfer of proteins to energy-making factories inside brain cells. The factories, known as mitochondria, need these proteins to maintain their function. When disruption of the supply line disables the mitochondria, brain cells die.
“We showed the problem could be fixed by making cells overproduce the proteins that make this transfer possible,” said Yano, assistant professor of neurological surgery, neurology and genetics. “We don’t know if this will work in humans, but it’s exciting to have a solid new lead on how this condition kills brain cells.”
The findings are available online in Nature Neuroscience.
Huntington’s disease is caused by a defect in the huntingtin gene, which makes the huntingtin protein. Life expectancy after initial onset is about 20 years.
Scientists have known for some time that the mutated form of the huntingtin protein impairs mitochondria and that this disruption kills brain cells. But they have had difficulty understanding specifically how the gene harms the mitochondria.
For the new study, Yano and collaborators at the University of Pittsburgh worked with mice that were genetically modified to simulate the early stages of the disorder.
Yano and her colleagues found that the mutated huntingtin protein binds to a group of proteins called TIM23. This protein complex normally helps transfer essential proteins and other supplies to the mitochondria. The researchers discovered that the mutated huntingtin protein impairs that process.
The problem seems to be specific to brain cells early in the disease. At the same point in the disease process, the scientists found no evidence of impairment in liver cells, which also produce the mutated huntingtin protein.
The researchers speculated that brain cells might be particularly reliant on their mitochondria to power the production and recycling of the chemical signals they use to transmit information. This reliance could make the cells vulnerable to disruption of the mitochondria.
Other neurodegenerative conditions, including Alzheimer’s disease and amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease, have been linked to problems with mitochondria. Scientists may be able to build upon these new findings to better understand these disorders.
(Source: news.wustl.edu)