1. Head injuries can alter hundreds of genes and lead to serious brain diseases

    March 23, 2017 by Ashley

    From the UCLA press release:

    Head injuries can harm hundreds of genes in the brain in a way that increases people’s risk for a wide range of neurological and psychiatric disorders, UCLA life scientists report.

    The researchers identified for the first time master genes that they believe control hundreds of other genes which are linked to Alzheimer’s disease, Parkinson’s disease, post-traumatic stress disorder, stroke, attention deficit hyperactivity disorder, autism, depression, schizophrenia and other disorders.

    Knowing what the master genes are could give scientists targets for new pharmaceuticals to treat brain diseases. Eventually, scientists might even be able to learn how to re-modify damaged genes to reduce the risk for diseases, and the finding could help researchers identify chemical compounds and foods that fight disease by repairing those genes.

    “We believe these master genes are responsible for traumatic brain injury adversely triggering changes in many other genes,” said Xia Yang, a senior author of the study and a UCLA associate professor of integrative biology and physiology.

    Genes have the potential to become any of several types of proteins, and traumatic brain injury can damage the master genes, which can then lead to damage of other genes.

    That process can happen in a couple of ways, said Yang, who is a member of UCLA’s Institute for Quantitative and Computational Biosciences. One is that the injury can ultimately lead the genes to produce proteins of irregular forms. Another is to change the number of expressed copies of a gene in each cell. Either change can prevent a gene from working properly. If a gene turns into the wrong form of protein, it could lead to Alzheimer’s disease, for example.

    “Very little is known about how people with brain trauma — like football players and soldiers — develop neurological disorders later in life,” said Fernando Gomez-Pinilla, a UCLA professor of neurosurgery and of integrative biology and physiology, and co-senior author of the new study. “We hope to learn much more about how this occurs.”

    The research appears in EBioMedicine, a journal published by Cell and The Lancet.

    The researchers trained 20 rats to escape from a maze. They then used a fluid to produce a concussion-like brain injury in 10 of the rats; the 10 others did not receive brain injuries. When the rats were placed in the maze again, those that had been injured took approximately 25 percent longer than the non-injured rats to solve it.

    To learn how the rats’ genes had changed in response to the brain injury, the researchers analyzed genes from five animals in each group. Specifically, they drew RNA from the hippocampus, which is the part of the brain that helps regulate learning and memory, and from leukocytes, white blood cells that play a key role in the immune system.

    In the rats that had sustained brain injuries, there was a core group of 268 genes in the hippocampus that the researchers found had been altered, and a core group of 1,215 genes in the leukocytes that they found to have been changed.

    “A surprise was how many major changes occurred to genes in the blood cells,” Yang said. “The changes in the brain were less surprising. It’s such a critical region, so it makes sense that when it’s damaged, it signals to the body that it’s under attack.”

    Nearly two dozen of the altered genes are present in both the hippocampus and the blood, which presents the possibility that scientists could develop a gene-based blood test to determine whether a brain injury has occurred, and that measuring some of those genes could help doctors predict whether a person is likely to develop Alzheimer’s or other disorders. The research could also lead to a better way to diagnose mild traumatic brain injury.

    More than 100 of the genes that changed after the brain injury have counterparts in humans that have been linked to neurological and psychiatric disorders, the researchers report. For example, 16 of the genes affected in the rats have analogs in humans, and those genes are linked to a predisposition for Alzheimer’s, the study reports. The researchers also found that four of the affected genes in the hippocampus and one in leukocytes are similar to genes in humans that are linked to PTSD.

    Yang said the study not only indicated which genes are affected by traumatic brain injury and linked to serious disease, but also might point to the genes that govern metabolism, cell communication and inflammation — which might make them the best targets for new treatments for brain disorders.

    The researchers now are studying some of the master genes to determine whether modifying them also causes changes in large numbers of other genes. If so, the master genes would be even more promising as targets for new treatments. They also plan to study the phenomenon in people who have suffered traumatic brain injury.

    In a 2016 study, Yang, Gomez-Pinilla and colleagues reported that hundreds of genes can be damaged by fructose and that an omega-3 fatty acid called docosahexaenoic acid, or DHA, seems to reverse the harmful changes produced by fructose. One of the genes they identified in that study, Fmod, also was among the master regulator genes identified in the new research.

    Not everyone with traumatic brain injuries develops the same diseases, but more severe injuries can damage more genes, said Gomez-Pinilla, who also is a member of UCLA’s Brain Injury Research Center.

     


  2. New risk factors for anxiety disorders

    March 20, 2017 by Ashley

    From the University of Würzburg press release:

    Mental, social and inherited factors all play a role in anxiety disorders. In the journal Molecular Psychiatry, a research team from Julius-Maximilians-Universität Würzburg (JMU) in Bavaria, Germany, describes a hitherto unknown genetic pathway for developing such diseases: They pinpointed at least four variants of the GLRB gene (glycine receptor B) as risk factors for anxiety and panic disorders. More than 5000 voluntary participants and 500 patients afflicted by panic disorder took part in the study that delivered these results.

    In Germany, around 15 percent of adults suffer from anxiety and panic disorders. Some people may have an extreme fear of spiders or other objects while others have breathing difficulties and accelerated heart beat in small rooms or large gatherings of people. With some afflicted persons, the anxiety attacks occur for no apparent cause. Many patients suffer from the detrimental impacts on their everyday lives — they often have problems at work and withdraw from social contacts.

    How are fear and anxiety triggered? How do anxiety disorders arise and evolve?

    Scientists from Münster, Hamburg and Würzburg have looked into these questions within the scope of Collaborative Research Center (CRC) TR 58 funded by Deutsche Forschungsgemeinschaft. Their goal is to develop new therapies that are better tailored to the individual patients. Anxiety disorders can be treated with drugs and behaviour therapy for instance.

    Gene triggers hyperekplexia

    The discovery that different variants of the GLRB gene are associated with anxiety disorders might also contribute to the development of improved therapies. The gene had been known to the researchers for some time, albeit only in connection with a different disease:

    “Some mutations of the gene cause a rare neurological disorder called hyperekplexia,” explains Professor Jürgen Deckert, member of the CRC and Director of the Department of Psychiatry at the JMU University Hospital. The patients are permanently hypertonic and show pronounced startle responses, which may even cause sufferers to fall involuntarily. Similar to persons suffering from anxiety disorders, these patients develop behaviour to avoid potentially frightening situations.

    The “fear network” in the brain is activated

    But the GLRB gene variants that have recently been associated with anxiety and panic disorders for the first time are different from the ones described above. They occur more frequently and presumably entail less severe consequences. But they, too, trigger overshooting startle responses, and as a result may excessively activate the brain’s “fear network.” High-resolution images of the brain activities of study participants provided the clues for the Würzburg scientists.

    “The results point to a hitherto unknown pathway of developing an anxiety disorder,” Deckert says. He believes that further investigations are now necessary to determine whether these findings can be harnessed to develop new or individual therapies. For example, it is conceivable to bring the “fear network” that is misregulated by the GLRB gene back on track by administering drugs.


  3. Study suggests social phobia may be affected by genes

    March 14, 2017 by Ashley

    From the University of Bonn press release:

    People with social anxiety avoid situations in which they are exposed to judgment by others. Those affected also lead a withdrawn life and maintain contact above all on the Internet. Around one in ten people is affected by this anxiety disorder over the course of their life. Researchers at the University of Bonn have now found evidence for a gene that is believed to be linked to the illness. It encodes a serotonin transporter in the brain. Interestingly, this messenger suppresses feelings of anxiety and depressiveness. The scientists want to investigate this cause more precisely and are thus looking for more study participants. The results will be published in the journal Psychiatric Genetics.

    Heart palpitations, trembling and shortness of breath: those who suffer from social phobia avoid larger groups. Verbal tests or everyday arrangements are filled with fear — after all, other people could make a negative judgement. Those affected often avoid such situations for this reason. Contact is often easier over social media or anonymously over the Internet. Social phobias are among the psychiatric disorders that are triggered simultaneously by genetic and environmental factors. “There is still a great deal to be done in terms of researching the genetic causes of this illness,” says Dr. Andreas Forstner from the Institute of Human Genetics at the University of Bonn. “Until now, only a few candidate genes have been known that could be linked to this.”

    Individual base pairs can vary in the DNA

    Together with the Clinic and Policlinic for Psychosomatic Medicine and Psychotherapy at the University Hospital Bonn, Dr. Forstner is conducting a study into the genetic causes of social phobia. The research team investigated the DNA of a total of 321 patients and compared it with 804 control individuals. The focus of the scientists lay on what are known as single nucleotide polymorphisms (SNPs). “There are variable positions in the DNA that can exist to various degrees in different people,” explains Dr. Forstner.

    The cause of genetic illnesses often lies in the SNPs. It is estimated that more than thirteen million such changes exist in the human DNA. The scientists investigated a total of 24 SNPs that are suspected in the widest sense of being the cause of social phobias and other mental disorders. “This is the largest association study so far into social phobia,” says associate professor (Privatdozent) Johannes Schumacher from the Institute of Human Genetics at the University of Bonn.

    Patients provided information about their symptoms

    Over the course of the study, scientists at the Clinic and Policlinic for Psychosomatic Medicine and Psychotherapy at the University Hospital Bonn will ask the patients about their symptoms and the severity of their social phobia. Their DNA is also examined using a blood sample. Whether there is a link between the signs of the illness and the genes is being investigated by the scientists using statistical methods. The evaluation of the previously collected data indicated that an SNP in the serotonin transporter gene SLC6A4 is involved in the development of social phobia.

    This gene encodes a mechanism in the brain that is involved in transporting the important messenger serotonin. This substance suppresses, among other things, feelings of fear and depressive moods. “The result substantiates indications from previous studies that serotonin plays an important role in social phobia,” says associate professor (Privatdozent) Dr. Rupert Conrad from the Clinic and Policlinic for Psychosomatic Medicine and Psychotherapy. Medications that block serotonin reuptake and increase the concentration of the messenger in the tissue fluid in the brain have already long been used to treat anxiety disorders and depression.

    Subjects can participate in expanded study

    The scientists now want to investigate more closely what the links are between the DNA and social phobia. “In order to achieve this goal, we need many more study participants who suffer from social anxiety,” says the psychologist and study coordinator Stefanie Rambau from the Clinic and Policlinic for Psychosomatic Medicine and Psychotherapy at University Hospital Bonn. Information about the study is available at http://www.SocialPhobiaResearch.de. “Those who take part will help to research social phobia. This is the basis of better diagnosis and treatment procedures in the future,” says Stefanie Rambau.


  4. ‘Sixth sense’ may be more than just a feeling

    September 29, 2016 by Ashley

    From the National Institutes of Health media release:

    regions of the brain correlated with more severe neurobehavioral symptomsWith the help of two young patients with a unique neurological disorder, an initial study by scientists at the National Institutes of Health suggests that a gene called PIEZO2 controls specific aspects of human touch and proprioception, a “sixth sense” describing awareness of one’s body in space. Mutations in the gene caused the two to have movement and balance problems and the loss of some forms of touch. Despite their difficulties, they both appeared to cope with these challenges by relying heavily on vision and other senses.

    “Our study highlights the critical importance of PIEZO2 and the senses it controls in our daily lives,” said Carsten G. Bönnemann, M.D., senior investigator at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and a co-leader of the study published in the New England Journal of Medicine. “The results establish that PIEZO2 is a touch and proprioception gene in humans. Understanding its role in these senses may provide clues to a variety of neurological disorders.”

    Dr. Bönnemann’s team uses cutting edge genetic techniques to help diagnose children around the world who have disorders that are difficult to characterize. The two patients in this study are unrelated, one nine and the other 19 years old. They have difficulties walking; hip, finger and foot deformities; and abnormally curved spines diagnosed as progressive scoliosis.

    Working with the laboratory of Alexander T. Chesler, Ph.D., investigator at NIH’s National Center for Complementary and Integrative Health (NCCIH), the researchers discovered that the patients have mutations in the PIEZO2 gene that appear to block the normal production or activity of Piezo2 proteins in their cells. Piezo2 is what scientists call a mechanosensitive protein because it generates electrical nerve signals in response to changes in cell shape, such as when skin cells and neurons of the hand are pressed against a table. Studies in mice suggest that Piezo2 is found in the neurons that control touch and proprioception.

    “As someone who studies Piezo2 in mice, working with these patients was humbling,” said Dr. Chesler. “Our results suggest they are touch-blind. The patient’s version of Piezo2 may not work, so their neurons cannot detect touch or limb movements.

    Further examinations at the NIH Clinical Center suggested the young patients lack body awareness. Blindfolding them made walking extremely difficult, causing them to stagger and stumble from side to side while assistants prevented them from falling. When the researchers compared the two patients with unaffected volunteers, they found that blindfolding the young patients made it harder for them to reliably reach for an object in front of their faces than it was for the volunteers. Without looking, the patients could not guess the direction their joints were being moved as well as the control subjects could.

    The patients were also less sensitive to certain forms of touch. They could not feel vibrations from a buzzing tuning fork as well as the control subjects could. Nor could they tell the difference between one or two small ends of a caliper pressed firmly against their palms. Brain scans of one patient showed no response when the palm of her hand was brushed.

    Nevertheless, the patients could feel other forms of touch. Stroking or brushing hairy skin is normally perceived as pleasant. Although they both felt the brushing of hairy skin, one claimed it felt prickly instead of the pleasant sensation reported by unaffected volunteers. Brain scans showed different activity patterns in response to brushing between unaffected volunteers and the patient who felt prickliness.

    Despite these differences, the patients’ nervous systems appeared to be developing normally. They were able to feel pain, itch, and temperature normally; the nerves in their limbs conducted electricity rapidly; and their brains and cognitive abilities were similar to the control subjects of their age.

    “What’s remarkable about these patients is how much their nervous systems compensate for their lack of touch and body awareness,” said Dr. Bönnemann. “It suggests the nervous system may have several alternate pathways that we can tap into when designing new therapies.

    Previous studies found that mutations in PIEZO2 may have various effects on the Piezo2 protein that may result in genetic musculoskeletal disorders, including distal arthrogryposis type 5, Gordon Syndrome, and Marden-Walker Syndrome. Drs. Bönnemann and Chesler concluded that the scoliosis and joint problems of the patients in this study suggest that Piezo2 is either directly required for the normal growth and alignment of the skeletal system or that touch and proprioception indirectly guide skeletal development.

    Our study demonstrates that bench and bedside research are connected by a two-way street,” said Dr. Chesler. “Results from basic laboratory research guided our examination of the children. Now we can take that knowledge back to the lab and use it to design future experiments investigating the role of PIEZO2 in nervous system and musculoskeletal development.”

    This work was supported by the NCCIH and NINDS intramural research programs.


  5. A microRNA plays role in major depression

    September 13, 2016 by Ashley

    From the University of Alabama at Birmingham media release:

    Depressed seniorA tiny RNA appears to play a role in producing major depression, the mental disorder that affects as many as 250 million people a year worldwide.

    Major depression, formally known as major depressive disorder, or MDD, brings increased risk of suicide and is reported to cause the second-most years of disability after low-back pain.

    University of Alabama at Birmingham researchers have found that amounts of this microRNA are significantly elevated in the brains of experimental rats with induced depression from corticosterone treatment, in the post-death brains of humans diagnosed with MDD and in peripheral blood serum from living patients with MDD, according to a study by led by Yogesh Dwivedi, Ph.D., the Elesabeth Ridgely Shook Endowed Professor and director of Translational Research, UAB Mood Disorders Program, Department of Psychiatry.

    This microRNA — miR-124-3p — is thus a potential therapeutic target for novel drug development, and it can serve as a putative biomarker for MDD pathogenesis.

    Micro RNAs, or miRNAs, interact with messenger RNA after the miRNA is exported from the cell nucleus and processed by a team of enzymes. MiRNAs are robust players of gene regulation in cells, and there are more than 1,300 different miRNAs at work in the brain.

    In previous work, Dwivedi and colleagues had seen that a set of miRNAs were coordinately regulated in the prefrontal cortex of the brains of MDD subjects. The prefrontal cortex, known for controlling the executive function of the brain, is critically involved in the response to stress, by regulating the endocrine glands known as the hypothalamic-pituitary-adrenal axis. The adrenal gland produces the stress hormone cortisol in humans and corticosterone in rodents.

    To see if stress plays a role in the coordinated regulation of prefrontal cortex miRNAs, the UAB researchers then turned to a rat depression model. They found that rats treated with corticosterone to induce depression-like behavior showed coordinated dysregulation of miRNAs in the prefrontal cortex, and the most significantly affected miRNA was miR-124-3p.

    Their current paper, previewed in the journal Neuropsychopharmacology, examined the relevance of miR-124-3p in MDD pathogenesis.

    Using computer analysis of genome sequences, the researchers:

    • Identified eight highly potential target genes for binding by miR-124-3p, genes whose function is also reported to be critical in brain physiology during stress and MDD pathogenesis. Four of these potential target genes were significantly down-regulated in the prefrontal cortex of corticosterone-treated rats, and this down-regulation inversely correlated with miR-124-3p levels.
    • Showed that the four genes that were significantly down-regulated have evolutionarily conserved miR-124-3p binding sites across a wide range of higher vertebrate species.

    In neuroblastoma cells grown in culture:

    • Overexpression of miR-124-3p caused significant down-regulation for two of the potential target genes.In prefrontal cortex neurons from depression-model rats treated with corticosterone:
    • Significant binding by miR-124-3p to two of the potential target genes was seen, as measured from immunoprecipitated RNA-induced silencing complexes.
    • The locus-specific origin of for mature miR-124-3p was identified at a site on chromosome 3, out of three possible chromosomal sites, and two CpG “islands” that can act as sites from epigenetic modification by DNA methylation were identified near the miR-124 gene promoter on chromosome 3.
    • This miR-124-3 promoter was found to be hypo-methylated in the corticosterone-treated rats, and the gene expression of one DNA methyltransferase — Dnmt3a — was significantly repressed.

    For humans:

    • In post-mortem brains of 15 controls and 15 MDD subjects, the MDD group showed significant increase in the expression of miR-124-3p, and expression of three of the potential target genes was significantly lower.
    • The level of miR-124-3p was significantly higher in the serum of 18 antidepressant-free MDD patients, as compared with 17 healthy controls.

    “Altogether,” the UAB researchers conclude, “this is the first comprehensive and mechanistic study at in-vitro and in-vivo levels which demonstrates that, not only are there consistent depression-associated changes in the expression of miR-124-3p across different species, but also the genes that are targets of this miRNA are highly dysregulated, showing altered response at functional level.”


  6. Altruism is favored by chance

    August 9, 2016 by Ashley

    From the University of Bath media release:

    sharing childrenWhy do we feel good about giving to charity when there is no direct benefit to ourselves, and feel bad about cheating the system? Mathematicians may have found an answer to the longstanding puzzle as to why we have evolved to cooperate.

    An international team of researchers, publishing in the Proceedings of the National Academy of Sciences, has found that altruism is favoured by random fluctuations in nature, offering an explanation to the mystery as to why this seemingly disadvantageous trait has evolved.

    The researchers, from the Universities of Bath, Manchester and Princeton (USA), developed a mathematical model to predict the path of evolution when altruistic “cooperators” live alongside “cheats” who use up resources but do not themselves contribute.

    Humans are not the only organisms to cooperate with one another. The scientists used the example of Brewer’s yeast, which can produce an enzyme called invertase that breaks down complex sugars in the environment, creating more food for all. However, those that make this enzyme use energy that could instead have been used for reproduction, meaning that a mutant “cheating” strain that waits for others to do the hard work would be able to breed faster as a result.

    Darwinian evolution suggests that their ability to breed faster will allow the cheats (and their cheating offspring) to proliferate and eventually take over the whole population. This problem is common to all altruistic populations, raising the difficult question of how cooperation evolved.

    Dr Tim Rogers, Royal Society University Research Fellow at the University of Bath, said: “Scientists have been puzzled by this for a long time. One dominant theory was that we act more favourably towards genetic relatives than strangers, summed up by J. S. Haldane’s famous claim that he would jump into a river to save two brothers or eight cousins.

    What we are lacking is an explanation of how these behaviours could have evolved in organisms as basic as yeast. Our research proposes a simple answer — it turns out that cooperation is favoured by chance.”

    The key insight is that the total size of population that can be supported depends on the proportion of cooperators: more cooperation means more food for all and a larger population. If, due to chance, there is a random increase in the number of cheats then there is not enough food to go around and total population size will decrease. Conversely, a random decrease in the number of cheats will allow the population to grow to a larger size, disproportionally benefitting the cooperators. In this way, the cooperators are favoured by chance, and are more likely to win in the long term.

    Dr George Constable, soon to join the University of Bath from Princeton, uses the analogy of flipping a coin, where heads wins £20 but tails loses £10:

    Although the odds winning or losing are the same, winning is more good than losing is bad. Random fluctuations in cheat numbers are exploited by the cooperators, who benefit more then they lose out.”


  7. Researchers identify new autism blood biomarker

    May 4, 2016 by Ashley

    From the UT Southwestern Medical Center media release:

    autism metaphorResearchers at UT Southwestern Medical Center have identified a blood biomarker that may aid in earlier diagnosis of children with autism spectrum disorder, or ASD.

    Early intervention is the key to the best treatment for ASD, which affects about 1 in 70 children. Unfortunately, most children are not diagnosed until about age 4, when communication and social disabilities become apparent. This neurodevelopmental disorder is characterized by social interaction and communication challenges, and restricted and repetitive patterns of behavior.

    In a recent edition of Scientific Reports, UT Southwestern researchers reported on the identification of a blood biomarker that could distinguish the majority of ASD study participants versus a control group of similar age range. In addition, the biomarker was significantly correlated with the level of communication impairment, suggesting that the blood test may give insight into ASD severity.

    “Numerous investigators have long sought a biomarker for ASD,” said Dr. Dwight German, study senior author and Professor of Psychiatry at UT Southwestern. “The blood biomarker reported here along with others we are testing can represent a useful test with over 80 percent accuracy in identifying ASD.”

    Since other studies have found abnormalities in the immune systems of autistic children, researchers set out to search for antibodies in the blood related to ASD. In this study, researchers found that boys with ASD had significantly reduced levels of a serum IgG1 antibody. Investigating further, researchers analyzed 25 peptoid compounds that bound to IgG1 and zeroed in on one — ASD1 — that was 66 percent accurate in diagnosing ASD. When combined with thyroid stimulating hormone level measurements, the ASD1-binding biomarker was 73 percent accurate at diagnosis.

    More testing, including analysis of blood samples from girls with ASD, is needed to further validate the findings, Dr. German said. Girls made up a small ratio of the study group, and the biomarker did not correlate as strongly with ASD diagnosis as with boys.


  8. Finding the Genetic Cause for Intellectual disability

    April 25, 2016 by Ashley

    From the Osaka University media release:

    geneticsA research group led by Osaka University and collaborative institutions discovered that disorders in the same gene PIGG are the cause for intellectual disability with seizures and hypotonia. PIGG is one of the enzymes active in the GPI anchor glycolipid synthesis and the current study revealed its significance in the development of the cerebral nervous system.

    Associate professor Yoshiko Murakami and her research team at the Research Institute for Microbial Diseases, Osaka University, together with other research groups from the University of Geneva (Switzerland), the University of Leeds (UK), Yamagata University and Yokohama City University based their discovery on an analysis of five patients from three families, who showed severe delays in psycho-motoric development and epilepsy and revealed the significance of PIGG in the development of the cerebral nervous system.

    Among the diseases that cause intellectual disorders with seizures and hypotonia, many causes of disorders remain unknown. Since variations in the PIGG gene have been discovered as one cause, it is now possible to diagnose PIGG deficiency for disorders for which diagnosis was not possible so far. With these research results the researchers hope to provide medical personnel and family members of patients with the opportunity to become aware of inherited GPI deficiencies and undergo examinations.

    The Research results were published in electronic version in the American Journal of Human Genetics on March 17 2016.

    In 2006, Murakami’s research group, together with a British research group with whom they conducted a joint research project, reported on the first inherited GPI deficiency (IGD), the PIGM deficiency. Based on the analysis using next-generation sequencers, the research was successively reported on since 2010 with IGD receiving attention as a new genetic disorder causing developmental delays and epilepsy.

    GPI anchors are glycolipids that anchor protein at a cell’s surface. They are synthesized through various enzymatic steps and added to protein. Even after having been added, they undergo various modifications and are transported to the cell’s surface. Protein groups of this shape are called GPI-anchored proteins with more than 150 different types known to exist with humans. 27 genes are involved in the biosynthesis and modification of GPI anchors. If these genes mutate and no GPI anchors are synthesized in all body cells, these 150 important proteins will turn defective, meaning that life would not be possible.

    So far, IGD has been reported with mutations of 13 genes among the 27. These are not cases of complete deficiency but partial deficiencies caused by function deterioration through mutation. Here symptoms arise due to decrease in various GPI anchored proteins that are transported to the surface of nerve cells as a result of mutation. This report presents the discovery of a PIGG deficiency as the IGD of the 14th gene.

    Unlike the other 13 genes, the GPI anchored proteins were transported as usual to the cell surface in cultured cells with normal structure, which is why the importance of PIGG’s existence remained unclear. However, the current research discovered that mutations of PIGG are the cause of severe cranial nerve problems and that PIGG plays an extremely important role in the actual development of the cerebral nervous system. This is expected to serve as a hint in advancing the analysis of its functions.


  9. Study finds increase in amyloid beta production when Alzheimer’s gene is present

    July 1, 2013 by Ashley

    From the Washington University School of Medicine in St. Louis press release by Michael C. Purdy via ScienceDaily:

    the brainScientists at Washington University School of Medicine in St. Louis have measured a significant and potentially pivotal difference between the brains of patients with an inherited form of Alzheimer’s disease and healthy family members who do not carry a mutation for the disease.

    Researchers have known that amyloid beta, a protein fragment, builds up into plaques in the brains of Alzheimer’s patients. They believe the plaques cause the memory loss and other cognitive problems that characterize the disease. Normal brain metabolism produces different forms of amyloid beta.

    The new study shows that research participants with genetic mutations that cause early-onset Alzheimer’s make about 20 percent more of a specific form of amyloid beta — known as amyloid beta 42 — than family members who do not have the Alzheimer’s mutation.

    Scientists found another, more surprising difference linked to amyloid beta 42 in mutation carriers: signs that amyloid beta 42 drops out of the cerebrospinal fluid much more quickly than other forms of amyloid beta. This may be because amyloid beta 42 is being deposited on brain amyloid plaques.

    These results indicate how much we should target amyloid beta 42 with Alzheimer’s drugs,” said Randall Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology. “We are hopeful that this and other research will lead to preventive therapies to delay or even possibly prevent Alzheimer’s disease.”

    The study appears June 12 in Science Translational Medicine.

    In addition to helping develop treatments for inherited Alzheimer’s, investigations of these conditions have helped scientists lay the groundwork for advances in treatment of the much more common sporadic forms of the disease.

    Three forms account for most of the amyloid beta found in the cerebrospinal fluid: amyloid beta 38, 40 and 42. Earlier studies of the human brain after death and using animal research had suggested that amyloid beta 42 was the most important contributor to Alzheimer’s. The new study not only confirms this connection but also quantifies overproduction of amyloid beta 42 for the first time in living human brains.

    Bateman, who co-developed a technique that measures the rate at which amyloid beta is produced and cleared from the cerebrospinal fluid, contacted several Washington University colleagues to see if they could develop a way to analyze the types of amyloid beta being produced in the brain.

    Bateman, metabolism expert Bruce Patterson, PhD, and biomedical engineer Donald Elbert, PhD, created a new mathematical model to describe the production and clearance of amyloid beta.

    The scientists applied the model to data from 11 research participants with Alzheimer’s mutations and 12 related family members who did not have the genetic errors that cause Alzheimer’s. The model let the scientists compare the production rates of the protein’s different forms, revealing an increase in amyloid beta 42 production in subjects with an Alzheimer’s gene.

    “Working in isolation, any one of us would likely have gotten the wrong answer, or no answer,” Elbert said. “Bringing our different skill sets together let us tackle a very complex physiological problem.”

    Scientists are testing the new model on data from approximately 100 Alzheimer’s patients.

    “We hope that our new insights about the production and clearance of amyloid beta proteins will pave the way for future studies aimed at understanding and altering the metabolic processes that underlie this devastating disease,” Patterson said.


  10. Study examines genetics of dyslexia and language impairment

    June 30, 2013 by Ashley

    From the Yale University press release by Karen N. Peart via ScienceDaily:

    studying problemsA new study of the genetic origins of dyslexia and other learning disabilities could allow for earlier diagnoses and more successful interventions, according to researchers at Yale School of Medicine. Many students now are not diagnosed until high school, at which point treatments are less effective.

    The study is published online and in the July print issue of the American Journal of Human Genetics. Senior author Dr. Jeffrey R. Gruen, professor of pediatrics, genetics, and investigative medicine at Yale, and colleagues analyzed data from more than 10,000 children born in 1991-1992 who were part of the Avon Longitudinal Study of Parents and Children (ALSPAC) conducted by investigators at the University of Bristol in the United Kingdom.

    Gruen and his team used the ALSPAC data to unravel the genetic components of reading and verbal language. In the process, they identified genetic variants that can predispose children to dyslexia and language impairment, increasing the likelihood of earlier diagnosis and more effective interventions.

    Dyslexia and language impairment are common learning disabilities that make reading and verbal language skills difficult. Both disorders have a substantial genetic component, but despite years of study, determining the root cause had been difficult.

    In previous studies, Gruen and his team found that dopamine-related genes ANKK1 and DRD2 are involved in language processing. In further non-genetic studies, they found that prenatal exposure to nicotine has a strong negative affect on both reading and language processing. They had also previously found that a gene called DCDC2 was linked to dyslexia.

    In this new study, Gruen and colleagues looked deeper within the DCDC2 gene to pinpoint the specific parts of the gene that are responsible for dyslexia and language impairment. They found that some variants of a gene regulator called READ1 (regulatory element associated with dyslexia1) within the DCDC2 gene are associated with problems in reading performance while other variants are strongly associated with problems in verbal language performance.

    Gruen said these variants interact with a second dyslexia risk gene called KIAA0319. “When you have risk variants in both READ1 and KIAA0319, it can have a multiplier effect on measures of reading, language, and IQ,” he said. “People who have these variants have a substantially increased likelihood of developing dyslexia or language impairment.”

    “These findings are helping us to identify the pathways for fluent reading, the components of those pathways; and how they interact,” said Gruen. “We now hope to be able to offer a pre-symptomatic diagnostic panel, so we can identify children at risk before they get into trouble at school. Almost three-quarters of these children will be reading at grade level if they get early intervention, and we know that intervention can have a positive lasting effect.”

    Other authors on the study include Natalie R. Powers, John D. Eicher, Falk Butter, Yong Kong, Laura L. Miller, Susan M. Ring, and Matthias Mann.

    This work was supported by the UK medical research council, the Wellcome Trust (092731), the Yale Center for Genome Analysis; and the National Institutes of Health (R01 NS043530 and F31 DC012270)