Posts tagged mutation
Articles and news from the latest research reports.
Evidence Mounts for Role of Mutated Genes in Development of Schizophrenia
Johns Hopkins researchers have identified a rare gene mutation in a single family with a high rate of schizophrenia, adding to evidence that abnormal genes play a role in the development of the disease.
The researchers, in a report published in the journal Molecular Psychiatry, say that family members with the mutation in the gene Neuronal PAS domain protein 3 (NPAS3) appear at high risk of developing schizophrenia or another debilitating mental illnesses.
Normally functioning NPAS3 regulates the development of healthy neurons, especially in a region of the brain known as the hippocampus, which appears to be affected in schizophrenia. The Johns Hopkins researchers say they have evidence that the mutation found in the family may lead to abnormal activity of NPAS3, which has implications for brain development and function.
"Understanding the molecular and biological pathways of schizophrenia is a powerful way to advance the development of treatments that have fewer side effects and work better than the treatments now available," says study leader Frederick C. Nucifora Jr., Ph.D., D.O., M.H.S., an assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. "We could definitely use better medicines."
Scientists Work To Unravel Mystery Behind Woman Who Doesn’t Grow
Twenty year old Brooke Greenberg hasn’t grown since age five. For the last 15 years mystified doctors have been unable to explain the cause for Brooke’s disorder that has kept her aging in check. At age twenty, she maintains the physical and mental appearance of a toddler.
Eric Shadt wants to solve this most bizarre of medical mysteries. Director of the Icahn Institute for Genomics and Multiscale Biology at the Mount Sinai Medical Center in New York, Shadt is leading research to uncover the genetic cause for Brooke’s condition.
Because hormones control many of the maturation processes, one of the first things the research team looked at was to see if Brooke’s own hormone levels might be abnormal. In a piece he wrote on Katie Couric’s website on whose show he and the Greenberg family recently appeared, Shadt explained that Brooke “has no apparent abnormalities in her endocrine system, no gross chromosomal abnormalities, or any of the other disruptions known to occur in humans that can cause developmental issues.”
The researchers are now painstakingly analyzing Brooke’s entire genome in search of unique mutations. Needless to say, it is a formidable undertaking. “Cracking the code on Brooke’s condition,” Shadt wrote, “is the proverbial searching for a needle in a haystack, since likely there is one or a small number of letters changed in Brooke’s genome that has caused her condition.”
First Alzheimer’s case has full diagnosis 106 years later
More than a hundred years after Alois Alzheimer identified Alzheimer’s disease in a patient an analysis of that original patient’s brain has revealed the genetic origin of their condition.
The brain specimen tested was discovered in a university basement late last century after a search by rival teams of academics.
"It is extremely satisfying to place this last piece in the medical puzzle that Auguste Deter, the first ever Alzheimer patient, presented us with,” said Professor Manuel Graeber, from the University of Sydney.
"It is not only of historical interest, however, as it ends any speculation about whether the disease is correctly named after Alois Alzheimer. Alzheimer’s ability to recognise this dementia more than a century ago provides compelling support for specialisation in medicine. Alzheimer was a founding father of neuropathology, an important medical specialty that is still underrepresented."
Professor Graeber, from the University’s Brain and Mind Research Institute, Sydney Medical School and the Faculty of Health Sciences, collaborated with Professor Ulrich Müller’s team from the Institute of Human Genetics of the University of Giessen in Germany to produce the molecular diagnosis recently published in Lancet Neurology.
For years scientists have been wondering whether the first case of Alzheimer’s disease had a genetic cause. In 1901 Auguste Deter, a middle-aged female patient at the Frankfurt Asylum with unusual symptoms, including short-term memory loss, came to the attention of Dr Alzheimer. When she died, Dr Alzheimer examined her brain and described the distinctive damage indicating a form of presenile dementia.
For decades the more than 200 slides that Alzheimer prepared from Deter’s brain were lost. Then in 1992, after Professor Graeber uncovered new information pointing to their location, two teams of medical researchers began a dramatic race to find them.
One team searched in Frankfurt but it was a team headed by Professor Graeber, then working at the Max Planck Institute for Neurobiology that finally located the material at the University of Munich in 1997.
The slides were examined and confirmed beyond doubt that Deter was suffering from Alzheimer’s disease, with large numbers of amyloid plaques and neurofribrillary tangles in the brain that are hallmarks of the disease. Until now a more sophisticated DNA analysis of the small amount of fragile material in single slides has not been possible.
Since their rediscovery, a significant number of brain slides have been under the official custodianship of Professor Graeber who has been at the University of Sydney since 2010. He is preparing a book on the material.
"We found a mutation whose ultimate effect is the formation of amyloid plaques. These plaques, which form between nerve cells and seem to suffocate them are the key diagnostic landmark of the disease."
Alzheimer’s disease represents one of the greatest health problems in industrialised societies today. An estimated 100 million dementia sufferers are predicted worldwide by 2050, the vast majority of whom will have Alzheimer’s disease.
95 percent of Alzheimer’s patients suffer late onset of the illness after they turn 65. Five percent fall ill before that age (early onset) and Auguste Deter belongs to this group.
"We have revealed that Auguste Deter is one of those in which early onset of the disease is caused by mutation in a single gene," said Professor Graeber.
Scientists Map Initial Anti-Aging Formula
A new study indicates that scientists have found a new way of delaying the aging process in mice, and they hope to replicate the finding in people.
The scientists published their findings in the journal Cell Metabolism. The research was built upon an earlier study that shed light on progeria, a rare genetic disease that prematurely ages one in four million babies.
A mutation was found in the Lamin A protein, which lines the nucleus in human cells, disrupting the repair process and accelerating aging. They also found that normal and healthy Lamin A binds to and activates the gene SIRT1, which has been long associated with longevity. If scientists can develop drugs that mimic Lamin A or increase the binding between Lamin A and SIRT1, this may lead to anti-aging drugs.
The team also examined if the binding efficiency was boosted with resveratrol, a compound found in the skin of red grapes. Mice fed with concentrated resveratrol fared significantly better than healthy mice that weren’t given it and the onset of aging was delayed and the life expectancy was extended. Mice with progeria lived 30% longer when fed with resveratrol compared with progerial mice not given the compound.
Protein regulation linked to intellectual disability
Genetics researchers at the University of Adelaide have solved a 40-year mystery for a family beset by a rare intellectual disability - and they’ve discovered something new about the causes of intellectual disability in the process.
While many intellectual disabilities are caused directly by a genetic mutation in the so-called “protein coding” part of our genes, the researchers found that in their case the answer laid outside the gene and in the regulation of proteins.
Protein regulation involves the switching on or off of a protein by specific genes. As a consequence in this case, either too much or too little of this protein can trigger the disability.
The team has studied a large (anonymous) Australian family of 100 people, who for generations have not known the source of their genetically inherited condition.
The disability - which results in a lower IQ, behavioural problems such as aggression, and memory loss, and is linked with developmental delays, epilepsy, schizophrenia and other problems - affects only the male family members and can be passed on by the female family members to their children.
Genetic samples taken from the family and laboratory testing involving mice have confirmed that the protein produced by the HCFC1 (host cell factor C1) gene is the cause of this disability.
"The causes of intellectual disability generally are highly variable and the genetic causes in particular are numerous. The vast majority of intellectual disabilities are due to genetic mutations in proteins, so it was rather unexpected that we found this particular disability to be due to a regulatory mutation," says the leader of the study, Professor Jozef Gecz from the University of Adelaide’s School of Paediatrics and Reproductive Health.
"We’ve been researching this specific disability for 10 years and it’s taken us the last three years to convince ourselves that the protein regulation is the key," he says.
"For the family, this means we now have a genetic test that will determine whether or not a female member of the family is a carrier, which brings various benefits for the family.
"From a scientific point of view, this widens our viewpoint on the causes of these disabilities and tells us where we should also look for answers for those families and individuals without answers.
"This is just the tip of the iceberg in understanding the impact of altered gene regulation on intellectual disability - the gene regulatory landscape is much bigger than the protein coding landscape. We have already found, and I would expect to continue finding, a number of other intellectual disabilities linked with protein regulation over the next 20 years or so."
Professor Gecz and his team have published their findings in this month’s issue of the American Journal of Human Genetics.
(Source: adelaide.edu.au)
Evolution of new genes captured
Like job-seekers searching for a new position, living things sometimes have to pick up a new skill if they are going to succeed. Researchers from the University of California, Davis, and Uppsala University, Sweden, have shown for the first time how living organisms do this.
The observation, published Oct. 19 in the journal Science, closes an important gap in the theory of natural selection.
Scientists have long wondered how living things evolve new functions from a limited set of genes. One popular explanation is that genes duplicate by accident; the duplicate undergoes mutations and picks up a new function; and, if that new function is useful, the gene spreads.
"It’s an old idea and it’s clear that this happens," said John Roth, a distinguished professor of microbiology at UC Davis and co-author of the paper.
The problem, Roth said, is that it has been hard to imagine how it occurs. Natural selection is relentlessly efficient in removing mutated genes: Genes that are not positively selected are quickly lost.
How then does a newly duplicated gene stick around long enough to pick up a useful new function that would be a target for positive selection?
Experiments in Roth’s laboratory and elsewhere led to a model for the origin of a novel gene by a process of “innovation, amplification and divergence.” This model has now been tested by Joakim Nasvall, Lei Sun and Dan Andersson at Uppsala.
Low-Dose Sedative Alleviates Autistic-Like Behavior in Mice With Dravet Syndrome Mutation
ScienceDaily (Aug. 22, 2012) — A low dose of the sedative clonazepam alleviated autistic-like behavior in mice with a mutation that causes Dravet syndrome in humans, University of Washington researchers have shown.
(Credit: © Vasiliy Koval / Fotolia)
Dravet syndrome is an infant seizure disorder accompanied by developmental delays and behavioral symptoms that include autistic features. It usually originates spontaneously from a gene mutation in an affected child not found in either parent.
Studies of mice with a similar gene mutation are revealing the overly excited brain circuits behind the autistic traits and cognitive impairments common in this condition. The research report appears in the Aug. 23 issue of Nature. Dr William Catterall, professor and chair of pharmacology at the UW, is the senior author.
Dravet syndrome mutations cause loss-of-function of the human gene called SCN1A. People or mice with two copies of the mutation do not survive infancy; one copy results in major disability and sometimes early death. The mutation causes malformation in one type of sodium ion channels, the tiny pores in nerve cells that produce electrical signals by gating the flow of sodium ions.
The Catteralll lab is studying these defective ion channels and their repercussion on cell-to-cell signaling in the brain. They also are documenting the behavior of mice with this mutation, compared to their unaffected peers. Their findings may help explain how the sporadic gene mutations that cause Dravet syndrome lead to its symptoms of cognitive deficit and autistic behaviors.
New genetic data shows humans and great apes diverged earlier than thought
To calculate when a species diverged, researchers look at the average age of members of the species when they give birth and mutation rates. The older the average age, the more time it takes for mutations to cause changes. Insects that produce offspring in a matter of months, for example, can adapt much more quickly to environmental changes than large animals that produce offspring many years after they themselves are born. To find such data for both chimps and gorillas, the research team worked with many groups in Africa that included studies of the animals that totaled 105 gorillas and 226 chimps. They also looked at fossilized excrement that contained DNA data. In so doing they found that the average age of giving birth for female chimps was 25 years old. They then divided the number of mutations found by the average age of birth to get the mutation rate. In so doing, they found it to be slower than humans, which meant that estimates based on it to calculate divergence times were likely off by as much as a million years.
The end result of the team’s research indicates that humans and chimps likely diverged some seven to eight million years ago, while the divergence of gorillas (which led to both humans and chimps) came approximately eight to nineteen million years ago. To put the numbers in perspective, humans and Neanderthals split just a half to three quarters of a million years ago.
The collapse of the Fukushima Dai-ichi Nuclear Power Plant caused a massive release of radioactive materials to the environment. A prompt and reliable system for evaluating the biological impacts of this accident on animals has not been available. Here we show that the accident caused physiological and genetic damage to the pale grass blue Zizeeria maha, a common lycaenid butterfly in Japan. We collected the first-voltine adults in the Fukushima area in May 2011, some of which showed relatively mild abnormalities. The F1 offspring from the first-voltine females showed more severe abnormalities, which were inherited by the F2 generation. Adult butterflies collected in September 2011 showed more severe abnormalities than those collected in May. Similar abnormalities were experimentally reproduced in individuals from a non-contaminated area by external and internal low-dose exposures. We conclude that artificial radionuclides from the Fukushima Nuclear Power Plant caused physiological and genetic damage to this species.
Scientists have developed a statistical method using evolutionary information to significantly enhance the likelihood of identifying disease-associated alleles in the genome that show better consistency across populations.
The group’s research appeared in the advanced online issue of the journal Molecular Biology and Evolution. The new method is now available to use via the web, so that researchers worldwide can apply it as an aid to discovering disease-associated mutations that are more consistently reproducible and therefore useable as diagnostic markers. Kumar refers to this new approach, combining standard comparative genomic studies with phylogenetic data as phylomedicine, a rapidly developing field that promises to streamline genomic information and improve its diagnostic power.
Read more: Evolutionary information improves discovery of mutations associated with diseases