Posts tagged genes

July 6, 2012

(Medical Xpress) — Scientists at the University of Liverpool have found that a protein produced by a gene identified in fruitflies, is responsible for communication between nerve cells in the brain.

Dr Stephen Royle: “This research is another step towards fully understanding the complexities of the human brain.”

The ‘stoned’ gene was discovered in fruitflies by scientists in the 1970s. When this gene was mutated, the flies had problems walking and flying, giving rise to the term ‘stoned’ gene. The same gene was found in mammals some years later, but until now scientists have not known precisely what this gene is responsible for and why it causes problems with physical functions when it mutates.

‘Packets of chemicals’

Scientists at Liverpool have found that the protein the gene expresses in mammals, called stonin2, is responsible for retrieving ‘packets’ of chemicals that nerve cells in the brain release in order to communicate with each other.  The inability of the gene to express this protein in the fruitfly study, suggests why the insect appeared not to be able to walk or fly normally.

The team used advanced techniques to inactivate stonin2 for short and long periods of time in animal cells grown in the laboratory. The cells used where from an area of the brain associated with learning and memory.  They showed that without stonin2 the nerve cells could not retrieve the ‘packets’ needed to transport the chemicals required for communications between nerve cells.

Dr Stephen Royle, from the University’s Institute of Translational Medicine, explains: “Nerve cells in the brain communicate by releasing ‘packets’ of chemicals.  These ‘packets’ must be retrieved and refilled with chemicals so that they can be used once again. This recycling programme is very important for nerve cells to keep communicating with each other. 

“We have shown that a protein called stonin 2 is needed for the packets to be retrieved. There is currently no evidence to suggest that the gene which expresses this protein is mutated in human disease, but any failure in its function would be disastrous.  The research is another step towards fully understanding the complexities of the human brain.”

The research is published in the journal, Current Biology.

Provided by University of Liverpool

Source: medicalxpress.com

June 28, 2012

In a genome-wide association (GWA) study, researchers from Boston University Schools of Medicine (BUSM) and Public Health (BUSPH) have identified several genes which influence degeneration of the hippocampus, the part of the brain most associated with Alzheimer disease (AD). The study, which currently appears online as a Rapid Communication in the Annals of Neurology, demonstrates the efficacy of endophenotypes for broadening the understanding of the genetic basis of and pathways leading to AD.

AD is a progressive neurodegenerative disorder for which there are no prevention methods. Available drugs only marginally affect disease severity and progression, making AD effectively untreatable.

GWA studies using very large samples have increased the number of robust associations to 10 genes, including APOE. However, these genes account for no more than 35 percent of the inherited risk of AD and most of the genetic underpinning of the disorder remains unexplained. According to the researchers, magnetic resonance imaging (MRI) of the brain provides in vivo quantitative measures of neurodegenerative and cerebrovascular brain injury that may represent AD-related changes long before clinical symptoms appear. These measures are more powerful than comparisons of individuals with AD with cognitively healthy persons because they avoid misclassification of normal persons who will develop disease in the future.

BUSM researchers conducted a two-stage GWA study for quantitative measures of hippocampal volume (HV), total cerebral volume (TCV) and white matter hyperintensities (WMH). Brain MRI measures of HV, TCV and WMH were obtained from 981 Caucasian and 419 African-American AD cases and their cognitively normal siblings in the MIRAGE (Multi Institutional Research in Alzheimer’s Genetic Epidemiology) Study. In addition, similar MRI measures were obtained from 168 AD cases, 336 individuals with mild cognitive impairment and 188 controls (all Caucasian) in the AD Neuroimaging Initiative (ADNI) Study. The MIRAGE Caucasian families and ADNI subjects were included in the first stage and the MIRAGE African American families were added in stage two. Results from the two Caucasians data sets were combined by meta-analysis.

In stage two, one genetic marker (i.e. single nucleotide polymorphism or SNP) from each of the gene regions that were most significantly associated with AD in the Caucasian data sets was evaluated in the African-American data set.

Novel genome-wide significant associations were observed for HV with SNPs in the APOE, F5/SELP, LHFP, and GCFC2 gene regions. All of these associations were supported by evidence in each data set.

"Our two-stage GWAS identified highly significant associations between a measure of degeneration in the brain region most strongly correlated with AD and several genes in both Caucasian and African American samples containing AD, cognitively impaired and cognitively healthy subjects. One of these associations was with the ε4 variant of APOE which is the most well-established genetic risk factor for AD.

Other associations were demonstrated with markers in F5/SELP, LHFP, and GCFC2, genes not previously implicated in this disease” explained senior author Lindsay Farrer, PhD, chief of biomedical genetics at BUSM. He also noted, “previous studies showed that blood level of P-selectin (the protein encoded by SELP) has been correlated with rate of cognitive decline in AD patients.”

Farrer believes it is very likely that the number and specificity of these associations will increase in future studies using larger samples and focused on additional precise structural and functional MRI measures. “These findings will inform experiments designed to increase our understanding of disease-causing mechanism and may lead to new therapeutics targets,” added Farrer.

Provided by Boston University Medical Center

Source: medicalxpress.com

ScienceDaily (June 24, 2012) — Hemimegalencephaly is a rare but dramatic condition in which the brain grows asymmetrically, with one hemisphere becoming massively enlarged. Though frequently diagnosed in children with severe epilepsy, the cause of hemimegalencephaly is unknown and current treatment is radical: surgical removal of some or all of the diseased half of the brain.

This image depicts hemimegalencephaly. (Credit: UC San Diego School of Medicine)

In a paper published in the June 24, 2012 online issue of Nature Genetics, a team of doctors and scientists, led by researchers at the University of California, San Diego School of Medicine and the Howard Hughes Medical Institute, say de novo somatic mutations in a trio of genes that help regulate cell size and proliferation are likely culprits for causing hemimegalencephaly, though perhaps not the only ones.

De novo somatic mutations are genetic changes in non-sex cells that are neither possessed nor transmitted by either parent. The scientists’ findings — a collaboration between Joseph G. Gleeson, MD, professor of neurosciences and pediatrics at UC San Diego School of Medicine and Rady Children’s Hospital-San Diego; Gary W. Mathern, MD, a neurosurgeon at UC Los Angeles’ Mattel Children’s Hospital; and colleagues — suggest it may be possible to design drugs that inhibit or turn down signals from these mutated genes, reducing or even preventing the need for surgery.

Gleeson’s lab studied a group of 20 patients with hemimegalencephaly upon whom Mathern had operated, analyzing and comparing DNA sequences from removed brain tissue with DNA from the patients’ blood and saliva.

"Mathern had reported a family with identical twins, in which one had hemimegalencephaly and one did not. Since such twins share all inherited DNA, we got to thinking that there may be a new mutation that arose in the diseased brain that causes the condition," said Gleeson. Realizing they shared the same ideas about potential causes, the physicians set out to tackle this question using new exome sequencing technology, which allows sequencing of all of the protein-coding exons of the genome at the same time.

The researchers ultimately identified three gene mutations found only in the diseased brain samples. All three mutated genes had previously been linked to cancers.

"We found mutations in a high percentage of the cells in genes regulating the cellular growth pathways in hemimegalencephaly," said Gleeson. "These same mutations have been found in various solid malignancies, including breast and pancreatic cancer. For reasons we do not yet understand, our patients do not develop cancer, but rather this unusual brain condition. Either there are other mutations required for cancer propagation that are missing in these patients, or neurons are not capable of forming these types of cancers."

The mutations were found in 30 percent of the patients studied, indicating other factors are involved. Nonetheless, the researchers have begun investigating potential treatments that address the known gene mutations, with the clear goal of finding a way to avoid the need for surgery.

"Although counterintuitive, hemimegalencephaly patients are far better off following the functional removal or disconnection of the enlarged hemisphere," said Mathern. "Prior to the surgery, most patients have devastating epilepsy, with hundreds of seizures per day, completely resistant to even our most powerful anti-seizure medications. The surgery disconnects the affected hemisphere from the rest of the brain, causing the seizures to stop. If performed at a young age and with appropriate rehabilitation, most children suffer less language or cognitive delay due to neural plasticity of the remaining hemisphere."

But a less-invasive drug therapy would still be more appealing.

"We know that certain already-approved medications can turn down the signaling pathway used by the mutated genes in hemimegalencephaly," said lead author and former UC San Diego post-doctoral researcher Jeong Ho Lee, now at the Korea Advanced Institute of Science and Technology. "We would like to know if future patients might benefit from such a treatment. Wouldn’t it be wonderful if our results could prevent the need for such radical procedures in these children?"

Source: Science Daily

ScienceDaily (June 14, 2012) — The first U.S. population prevalence study of mutations in the gene that causes fragile X syndrome, the most common inherited form of intellectual disability, suggests the mutation in the gene — and its associated health risks — may be more common than previously believed.

Writing this month (June 2012) in the American Journal of Medical Genetics, a team of Wisconsin researchers reports that the cascade of genetic amino acid repeats, which accumulate over generations and culminate in the mutation of a single gene causing fragile X, is occurring with more frequency among Americans than previously believed. The study also shows that as the genetic basis for the condition is passed from generation to generation and amplified, risks to neurological and reproductive health emerge in many carriers.

"The premutation of this condition is much more prevalent than we previously thought and there are some clinical risks associated with that," explains Marsha Mailick Seltzer, director of the University of Wisconsin-Madison Waisman Center, who led the new study.

Fragile X is caused by the unexplained runaway expansion of a set of amino acid repeats in a single X chromosome gene known as FMR1. When fully mutated, the gene fails to express and produce a protein that’s required for healthy brain development. The syndrome, which is more common in boys, results in a spectrum of intellectual disability.

However, before the gene fully mutates, carriers of the faulty gene exhibit a smaller number of elevated repeats, which expand as the gene is passed from generation to generation. Normal FMR1 genes exhibit anywhere from five to 40 repeats. Carriers with a premutation may have anywhere from 55 to 200. Those with between 45 and 54 repeats are characterized as falling into a “gray zone.” Carriers of gray zone expansions often pass the mutation on to their children who themselves are at greater risk of having the premutation, and in subsequent generations the risk of a full mutation causing fragile X syndrome is high.

The goal of the new study was to calculate the prevalence in a U.S. population of the premutation and the gray zone. The research was based on data from the Wisconsin Longitudinal Study (WLS), also known as the “Happy Days study,” which for more than 50 years has tracked the careers, family life, health and education of more than 10,000 graduates of Wisconsin’s high school class of 1957.

Using genetic samples from 6,747 WLS participants, the team led by Seltzer, an expert on developmental disability and family life, found that 1 in 151 females and 1 in 468 males carry the fragile X premutation while 1 in 35 females and 1 of every 42 males fall into the gray zone.

"The prevalence is high, the second highest reported in the world literature," says Seltzer, noting that the incidence of fragile X varies by population and is higher in some places such as Israel, and lower in others like Asia.

The expansion of the FMR1 gene is known to vary across ethnic groups. The sample in the WLS study is primarily white and of northern European descent.

People with the premutation are more likely to have a child with disability; to have neurological symptoms such as numbness, dizziness and faintness; and, for women, to experience early menopause. Although these symptoms have been recognized previously in clinical studies, the WLS data represent an unbiased sample and supports those observations.

"This study confirms that there are health risks associated with the premutation," says Seltzer. "People with the premutation have a higher probability of neurological and reproductive problems. There is a significant public health burden."

Source: Science Daily

ScienceDaily (May 31, 2012) — When flies are made to lose a gene with links to Restless Legs Syndrome (RLS), they suffer the same sleep disturbances and restlessness that human patients do. The findings reported online on May 31 in Current Biology, a Cell Press publication, strongly suggest a genetic basis for RLS, a condition in which patients complain of an irresistible urge to move that gets worse as they try to rest.

"Although widely prevalent, RLS is a disorder whose pathophysiological basis remains very poorly understood," said Subhabrata Sanyal of Emory University School of Medicine. "The major significance of our study is to highlight the fact that there might be a genetic basis for RLS. Understanding the function of these genes also helps to understand and diagnose the disease and may offer more focused therapeutic options that are currently limited to very general approaches."

Sanyal’s team recognized that a number of genome-wide association studies in humans had suggested connections between RLS and variation in a single gene (BTBD9).

"BTBD9 function or its relationship to RLS and sleep were a complete mystery," Sanyal said.

His team realized that there might be a way to shed some light on that mystery in fruit flies. Flies have a single, highly conserved version of the human BTBD9. They decided to test whether the gene that had turned up in those human studies would have any effect on sleep in the insects. In fact, flies need sleep just like humans do, and their sleep patterns are influenced by the same kinds of brain chemistry.

The researchers now report that flies lacking their version of the RLS-associated gene do lose sleep as they move more. When those flies were treated with a drug used for RLS, they showed improvements in their sleep.

The studies also yielded evidence about how the RLS gene works by controlling dopamine levels in the brain as well as iron balance in cells. Sanyal said his team will continue to explore other RLS-related genes that have been identified in human studies in search of more details of their interaction and function.

"Our results support the idea that genetic regulation of dopamine and iron metabolism constitute the core pathophysiology of at least some forms of RLS," the researchers write.

More broadly, they say, the study emphasizes the utility of simple animals such as fruit flies in unraveling the genetics of sleep and sleep disorders.

Source: Science Daily

ScienceDaily (May 30, 2012) — The same gene variations that make it difficult to stop smoking also increase the likelihood that heavy smokers will respond to nicotine-replacement therapy and drugs that thwart cravings, a new study shows.

High-risk genetic variations can increase the risk for nicotine dependence, but the same gene variants predict a more robust response to anti-smoking medications. (Credit: Li-Shiun Chen)

The research, led by investigators at Washington University School of Medicine in St. Louis, will appear online May 30 in the American Journal of Psychiatry.

The study suggests it may one day be possible to predict which patients are most likely to benefit from drug treatments for nicotine addiction.

"Smokers whose genetic makeup puts them at the greatest risk for heavy smoking, nicotine addiction and problems kicking the habit also appear to be the same people who respond most robustly to pharmacologic therapy for smoking cessation," says senior investigator Laura Jean Bierut, MD, professor of psychiatry. "Our research suggests that a person’s genetic makeup can help us better predict who is most likely to respond to drug therapy so we can make sure those individuals are treated with medication in addition to counseling or other interventions."

For the new study, the researchers analyzed data from more than 5,000 smokers who participated in community-based studies and more than 1,000 smokers in a clinical treatment study. The scientists focused on the relationship between their ability to quit smoking successfully and genetic variations that have been associated with risk for heavy smoking and nicotine dependence.

"People with the high-risk genetic markers smoked an average of two years longer than those without these high-risk genes, and they were less likely to quit smoking without medication," says first author Li-Shiun Chen, MD, assistant professor of psychiatry at Washington University. "The same gene variants can predict a person’s response to smoking-cessation medication, and those with the high-risk genes are more likely to respond to the medication."

In the clinical treatment trial, individuals with the high-risk variants were three times more likely to respond to drug therapy, such as nicotine gum, nicotine patches, the antidepressant buproprion and other drugs used to help people quit.

Tobacco use is the leading cause of preventable illness and death in the United States and a major public health problem worldwide. Cigarette smoking contributes to the deaths of an estimated 443,000 Americans each year. Although lung cancer is the leading cause of smoking-related cancer death among both men and women, tobacco also contributes to other lung problems, many other cancers and heart attacks.

Bierut and Chen say that the gene variations they studied are not the only ones involved in whether a person smokes, becomes addicted to nicotine or has difficulty quitting. But they contend that because the same genes can predict both heavy smoking and enhanced response to drug treatment, the genetic variants are important to the addiction puzzle.

"It’s almost like we have a ‘corner piece’ here," Bierut says. "It’s a key piece of the puzzle, and now we can build on it. Clearly these genes aren’t the entire story — other genes play a role, and environmental factors also are important. But we’ve identified a group that’s responding to pharmacologic treatment and a group that’s not responding, and that’s a key step in improving, and eventually tailoring, treatments to help people quit smoking."

Since people without the risky genetic variants aren’t as likely to respond to drugs, Bierut says they should get counseling or other non-drug therapies.

"This is an actionable genetic finding," Chen says. "Scientific journals publish genetic findings every day, but this one is actionable because treatment could be based on a person’s genetic makeup. I think this study is moving us closer to personalized medicine, which is where we want to go."

And Bierut says that although earlier studies suggested the genes had only a modest influence on smoking and addiction, the new clinical findings indicate the genetic variations are having a big effect on treatment response.

"These variants make a very modest contribution to the development of nicotine addiction, but they have a much greater effect on the response to treatment. That’s a huge finding," she says.

Source: Science Daily