Gene

Why a Lucky Few Can Eat to Their Heart’s Content.

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We all know people who seem to have been born with good genes—they may smoke, never exercise, or consume large amounts of bacon, yet they remain seemingly healthy. Now, researchers have found that individuals who carry a rare genetic mutation that controls the blood levels of certain fats, or lipids, are protected from heart disease. The result, reported here yesterday at the annual meeting of the American Society of Human Genetics, suggests that a drug mimicking this effect could prevent heart disease, a major killer.

Triglycerides are lipids that the body makes from unused calories in food and later burns as fuel. Doctors often monitor patients’ blood levels of these compounds because higher levels have been linked to a greater risk of heart disease.

One player in processing triglycerides is a protein called ApoC-III that is encoded by the gene APOC3. Five years ago, researchers discovered a mutation in APOC3 in 5% of the Amish population in Lancaster County, Pennsylvania. Those with this variant had unusually low levels of triglycerides after consuming a fat-laden milkshake. They also had only half as much ApoC-III protein in their blood, and they were less likely to develop calcification of coronary arteries, which can lead to coronary heart disease.

The Amish group was too small to allow researchers to directly link the genetic mutation to less heart disease, however. And it wasn’t clear whether the gene would show up in non-Amish people.

Now, researchers have found APOC3 mutations in the general U.S. population. They sequenced the protein-coding DNA, or exomes, of 3734 white and African-American volunteers, then combed through the data for genetic variants linked to triglyceride levels. A few people turned out to have either the Amish APOC3 mutation or one of three other variants in APOC3 that also disable this copy of the gene. When the team checked the DNA of a larger group of nearly 111,000 people, they found that about one in 200 carried one of the four APOC3 variants, reported Jacy Crosby of the University of Texas Health Science Center, Houston, who represented a large consortium called the National Heart, Lung, and Blood Institute Exome Sequencing Project.

The 500 or so people with one of these APOC3 variants not only had less ApoC-III in their blood and 38% lower triglyceride levels than the average person; they also had a 40% lower risk of coronary heart disease, whose effects include heart attacks. This result firms up the link between APOC3 and heart disease and also supports a possible prevention strategy, Crosby said: Reducing levels of the ApoC-III protein could potentially lower lipid levels and protect against heart disease. One such drug is already in clinical testing, she noted.

The new study “is exciting, but one has to be cautious” about whether such a drug will work, says geneticist Stephen Rich of the University of Virginia in Charlottesville. That’s because inhibiting ApoC-III late in life may not mimic being born with an APOC3 mutation, which protects for a lifetime, he says.

Faces are sculpted by ‘junk DNA’

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Scientists have identified thousands of regions in the genome that control the activity of genes for facial features.

Smiling child

‘Transcriptional enhancers‘ switch genes on or off in different parts of the face. Photograph: Rex Features

Researchers have started to figure out how DNA fine-tunes faces. In experiments on mice, they have identified thousands of regions in the genome that act like dimmer switches for the many genes that code for facial features, such as the shape of the skull or size of the nose.

Specific mutations in genes are already known to cause conditions such as cleft lips or palates. But in the latest study, a team of researchers led by Axel Visel of the Lawrence Berkeley National Laboratory in Berkeley, California, wanted to find out how variations seen across the normal range of faces are controlled.

Though everybody’s face is unique, the actual differences are relatively subtle. What distinguishes us is the exact size and position of things like the nose, forehead or lips. Scientists know that our DNA contains instructions on how to build our faces, but until now they have not known exactly how it accomplishes this.

Visel’s team was particularly interested in the portion of the genome that does not encode for proteins – until recently nicknamed “junk” DNA – but which comprises around 98% of our genomes. In experiments using embryonic tissue from mice, where the structures that make up the face are in active development, Visel’s team identified more than 4,300 regions of the genome that regulate the behaviour of the specific genes that code for facial features.

The results of the analysis are published on Thursday in Science.

These “transcriptional enhancers” tweak the function of hundreds of genes involved in building a face. Some of them switch genes on or off in different parts of the face, others work together to create, for example, the different proportions of a skull, the length of the nose or how much bone there is around the eyes.

“If you think about face development, a gene that is important for both development of the nose and the mouth might have two different enhancers and one of them activates the gene in the nose and the other just in the mouth,” said Visel.

“Certainly, one evolutionary advantage that is associated with this is that you can now change the sequence of the nose or mouth enhancers and, independently, affect the activity of the gene in just one structure or the other. It may be a way a way that nature has evolved in which you can fine-tune the expression of genes in complex ways without having to mess with the gene itself. If you destroy the protein itself that usually has much more severe consequences.”

In further experiments to test their findings, the scientists genetically engineered mice to lack three of the enhancers they had identified. They then used CT (computed tomography) scanning to build 3D images of the resulting mouse skulls at the age of eight weeks.

Compared with normal mice, the skulls of the modified mice had microscopic, but consistent, changes in the length and width of the faces, as expected. Importantly, all of the modified mice only showed subtle changes in their faces, and there were no serious harmful results such as cleft lips or palates.

Though the work was done in mice, Visel said that the lessons transfer across to humans very well. “When you look at the anatomy and development of the mouse versus the human, we find that the faces are actually very similar. Both are mammals and they have, essentially, all the same major bones and structures in their skulls, they just have a somewhat different shape in the mouse. The same genes that are important for mouse face development are important in humans.”

Visel said that the primary use of this information, beyond basic genetic knowledge, would be as part of a diagnostic tool, for clinicians who might be able to advise parents if they are likely to pass on particular mutations to their children.

Peter Hammond, a professor of computational biology at University College London‘s Institute of Child Health, who researches genetic effects on facial development, said understanding how faces develop can be important for health.

“There are many genetic conditions where the face is a first clue to diagnosis, and even though the facial differences are not necessarily severe the condition may involve significant intellectual impairment or adverse behavioural traits, as well as many other effects,” he said. “Diagnosis is important for parents as it reduces the stress of not knowing what is wrong, but also can be important for prognosis.”

The technology to go beyond diagnosis and make precise corrections of the genome does not yet exist and, even if it did, it is not clear that changing genes or enhancers to create “designer” faces would be worthwhile. “I don’t think it would be desirable to even attempt that. It’s certainly not something that motivates me to work on this,” said Visel. “And I don’t think anyone working in this field would seriously view this as a possible motivation.”

Metabolism ‘obesity excuse’ true

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Obese child

The mocked “obesity excuse” of being born with a slow metabolism is actually true for some people, say researchers.

A team at the University of Cambridge has found the first proof that mutated DNA does indeed slow metabolism.

The researchers say fewer than one in 100 people are affected and are often severely obese by early childhood.

The findings, published in the journal Cell, may lead to new obesity treatments even for people without the mutation.

Scientists at the Institute of Metabolic Science, in Cambridge, knew that mice born without a section of DNA, a gene called KSR2, gained weight more easily.

It slows the ability to burn calories and that’s important as it’s a new explanation for obesity”

Prof Sadaf Farooqi University of Cambridge

But they did not know what affect it may be having in people, so they analysed the DNA of 2,101 severely obese patients.

Some had mutated versions of KSR2.

It had a twin effect of increasing their appetite while their slowing metabolism.

“You would be hungry and wanting to eat a lot, you would not want to move because of a slower metabolism and would probably also develop type 2 diabetes at a young age,” lead researcher Prof Sadaf Farooqi told the BBC.

She added: “It slows the ability to burn calories and that’s important as it’s a new explanation for obesity.”

Munching on chips
The mutation delivers a double-whammy by increasing the drive to eat and reducing calorie burn

KSR2 is mostly active in the brain and it affects the way individual cells interpret signals, such as the hormone insulin, from the blood. This in turn affects the body’s ability to burn calories.

Prof Farooqi said the metabolism argument had been derided by doctors, as well as wider society, due to a lack of evidence that metabolism was slowed in obese patients. In many cases obese patients have an elevated metabolism to cope with fuelling a much larger body.

She said less than 1% of people had mutated versions of the gene and some would be a normal weight, but about 2% of children who were obese by the age of five would have the mutated gene.

However, if drugs could be developed to target problems with KSR2, then it might be beneficial to anyone who is too fat.

“Other genetic disorders, such as in blood pressure, have shown that even where there’s a normal gene, targeting the pathway can still help,” Prof Farooqi said.

The amount and types of food eaten, as well as levels of exercise, directly affect weight, but some people at more risk of becoming obese that others.

Obesity can run in families. The other obesity genes that have been discovered tend to affect appetite.

People have two copies of the FTO gene – one from each parent – and each copy comes in a high- and a low-risk form. Those with two-high risk copies of the FTO gene are thought to be 70% more likely to become obese than those with low-risk genes.

It makes fatty foods more tempting and alters levels of the hunger hormone ghrelin.

Dr Katarina Kos, from the University of Exeter Medical School, said: “It is an exciting and interesting breakthrough, this is a new pathway predisposing people to obesity.

“But it does exist in obese and lean people so you still need the obesogenic environment.”

The New Deadliest Substance Known to Man Is Top Secret (For Now)

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Scientists recently discovered a new type of botulinum toxin (a.k.a. botox) that they believe is the deadliest substance known to man. Because they’ve yet to discover an antitoxin, researchers won’t publish the details of gene sequence due to security concerns—a first for the scientific community. Thank God.

When scientists say this stuff is deadly, they mean it. It takes an injection of just 2 billionths of a gram or inhaling 13 billionths of a gram to kill an adult. A spoonful of the stuff in a city’s water supply could be catastrophic. The toxin, which comes from the bacterium Clostridium botulinum, blocks the chemical that makes nerves work, causing botulism and death by paralysis. In a comment accompanying a newly published journal article on the new botox, Stanford Medical School professor David Relman said the substance posed “an immediate and unusually serious risk to society.”

You’d be right to wonder: If this stuff is so dangerous, why do we have it in the first place? Well, it’s not manmade if that’s what you’re thinking. Before this new discovery, there were seven known branches on the botulinum family tree, but researchers recently found an eighth type of toxin in stool samples of an infant with botulism. It just so turns out that eighth type, known as type H, is the deadliest substance in the world. Scientists are withholding the genetic sequence so that terrorists, for instance, can’t synthesize it and do something terrible. Terrorists do like botox, too. It was one of these toxins that the Japanese cult Aum Shinrikyo tried to release in downtown Tokyo in the 1990s.

Despite the somewhat sensational nature of this latest discovery, everything is okay for now. This is, however, a rude reminder of how scientific discoveries can always be twisted into weapons of warfare. Unless we keep them secret, that is.

Researchers identify key proteins that help establish cell function

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Researchers at the University of California, San Diego School of Medicine have developed a new way to parse and understand how special proteins called “master regulators” read the genome, and consequently turn genes on and off.

Writing in the October 13, 2013 Advance Online Publication of Nature, the scientists say their approach could make it quicker and easier to identify specific gene associated with increased – an essential step toward developing future targeted treatments, preventions and cures for conditions ranging from diabetes to neurodegenerative disease.

“Given the emerging ability to sequence the genomes of individual patients, a major goal is to be able to interpret that DNA sequence with respect to disease risk. What diseases is a person genetically predisposed to?” said principal investigator Christopher Glass, MD, PhD, a professor in the departments of Medicine and Cellular and Molecular Medicine at UC San Diego.

“Mutations that occur in protein-coding regions of the genome are relatively straight forward, but most mutations associated with disease risk actually occur in regions of the genome that do not code for proteins,” said Glass. “A central challenge has been developing a strategy that assesses the potential functional impact of these non-coding mutations. This paper lays the foundation for doing so by examining how natural genetic variation alters the function of genomic regions controlling gene expression in a cell specific-manner.”

Cells use hundreds of different proteins called transcription factors to “read” the genome, employing those instructions to turn genes on and off. These factors tend to be bound close together on the genome, forming functional units called “enhancers.” Glass and colleagues hypothesized that while each cell has tens of thousands of enhancers consisting of myriad combinations of factors, most enhancers are established by just a handful of special transcription factors called “master regulators.” These master regulators play crucial, even disproportional, roles in defining each cell’s identity and function, such as whether it will be a muscle, skin or heart cell.

“Our main idea was that the binding of these master regulators is necessary for the co-binding of the other transcription factors that together enable enhancers to regulate the expression of nearby genes,” Glass said.

The scientists tested and validated their hypothesis by looking at the effects of approximately 4 million DNA sequence differences affecting master regulators in macrophage cells in two strains of mice. Macrophages are a type of immune response cell. They found that DNA sequence mutations deciphered by master regulators not only affected how they bound to the genome, but also impacted neighboring needed to make functional .

The findings have practical importance for scientists and doctors investigating the genetic underpinnings of disease, said Glass. “Without actual knowledge of where the master regulator binds, there is relatively little predictive value of the DNA sequence for non-coding variants. Our work shows that by collecting a focused set of data for the master regulators of a particular cell type, one can greatly reduce the ‘search space’ of the in a particular cell type that would be susceptible to the effects of mutations. This allows prioritization of mutations for subsequent analysis, which can lead to new discoveries and real-world benefits.”

Source:  University of California – San Diego

Girl who feels no pain could inspire new painkillers.

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A girl who does not feel physical pain has helped researchers identify a gene mutation that disrupts pain perception. The discovery may spur the development of new painkillers that will block pain signals in the same way.

People with congenital analgesia cannot feel physical pain and often injure themselves as a result – they might badly scald their skin, for example, through being unaware that they are touching something hot.

By comparing the gene sequence of a girl with the disorder against those of her parents, who do not, Ingo Kurth at Jena University Hospital in Germany and his colleagues identified a mutation in a gene called SCN11A.

This gene controls the development of channels on pain-sensing neurons. Sodium ions travel through these channels, creating electrical nerve impulses that are sent to the brain, which registers pain.

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Blocked signals

Overactivity in the mutated version of SCN11A prevents the build-up of the charge that the neurons need to transmit an electrical impulse, numbing the body to pain. “The outcome is blocked transmission of pain signals,” says Kurth.

To confirm their findings, the team inserted a mutated version of SCN11A into mice and tested their ability to perceive pain. They found that 11 per cent of the mice with the modified gene developed injuries similar to those seen in people with congenital analgesia, such as bone fractures and skin wounds. They also tested a control group of mice with the normal SCN11A gene, none of which developed such injuries.

The altered mice also took 2.5 times longer on average than the control group to react to the “tail flick” pain test, which measures how long it takes for mice to flick their tails when exposed to a hot light beam. “What became clear from our experiments is that although there are similarities between mice and men with the mutation, the degree of pain insensitivity is more prominent in humans,” says Kurth.

The team has now begun the search for drugs that block the SCN11Achannel. “It would require drugs that selectively block this but not other sodium channels, which is far from simple,” says Kurth.

Completely unexpected

“This is a cracking paper, and great science,” says Geoffrey Woods of the University of Cambridge, whose team discovered in 2006 that mutations in another, closely related ion channel gene can cause insensitivity to pain. “It’s completely unexpected and not what people had been looking for,” he says.

Woods says that there are three ion channels, called SCN9A, 10A and 11A, on pain-sensing neurons. People experience no pain when either of the first two don’t work, and agonising pain when they’re overactive. “With this new gene, it’s the opposite: when it’s overactive, they feel no pain. So maybe it’s some kind of gatekeeper that stops neurons from firing too often, but cancels pain signals completely when it’s overactive,” he says. “If you could get a drug that made SCN11A overactive, it should be a fantastic analgesic.”

“It’s fascinating that SCN11A appears to work the other way, and that could really advance our knowledge of the role of sodium channels in pain perception, which is a very hot topic,” says Jeffrey Mogil at McGill University in Canada, who was not involved in the new study.

Source: http://www.newscientist.com

Gene mutation may contribute to body weight regulation, obesity.

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Through mice and human studies, researchers at Boston Children’s Hospital suggest that a rare genetic mutation which can contribute to severe obesity could lead to further questions about weight gain and energy expenditure among obese patients.

“We found other mutations that weren’t as clearly damaging to the gene,” researcherJoseph Majzoub, MD, chief of endocrinology at Boston Children’s Hospital, said in a press release. “It’s possible that some of these more common mutations actually are pathogenic, especially in combination with other genes in the same pathway.”

According to researchers, the loss of either melanocortin-2 receptor (MC2R) or melanocortin receptor accessory protein (MRAP) in humans can cause severe resistance to adrenocorticotropic hormone, resulting in glucocorticoid deficiency. To study whether changes to melanocortin receptor accessory protein-2 (MRAP2) are associated with human obesity, Majzoub and colleagues conducted coding sequences in obese and control patients from the Genetics of Obesity Study cohort and the Swedish Obese Children’s Cohort.

Four rare heterozygous variants were absent from cohort-specific controls and 1,000 genomes were found in “unrelated, nonsyndromic, severely obese individuals, with all but one variant in the C-terminal region of the protein,” researchers wrote.

Although the rare mutations directly cause obesity in less than 1% of the obese population, other suspected mutations could be more likely to causeobesity, researchers wrote. These findings suggest that MRAP2 disruption could contribute to body weight regulation, prompting a need for further research to confirm these data.

Source: Endocrine Today

 

A Novel Channelopathy in Pulmonary Arterial Hypertension.

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BACKGROUND

Pulmonary arterial hypertension is a devastating disease with high mortality. Familial cases of pulmonary arterial hypertension are usually characterized by autosomal dominant transmission with reduced penetrance, and some familial cases have unknown genetic causes.

METHODS

We studied a family in which multiple members had pulmonary arterial hypertension without identifiable mutations in any of the genes known to be associated with the disease, including BMPR2, ALK1, ENG, SMAD9, and CAV1. Three family members were studied with whole-exome sequencing. Additional patients with familial or idiopathic pulmonary arterial hypertension were screened for the mutations in the gene that was identified on whole-exome sequencing. All variants were expressed in COS-7 cells, and channel function was studied by means of patch-clamp analysis.

RESULTS

We identified a novel heterozygous missense variant c.608 G→A (G203D) in KCNK3 (the gene encoding potassium channel subfamily K, member 3) as a disease-causing candidate gene in the family. Five additional heterozygous missense variants in KCNK3 were independently identified in 92 unrelated patients with familial pulmonary arterial hypertension and 230 patients with idiopathic pulmonary arterial hypertension. We used in silico bioinformatic tools to predict that all six novel variants would be damaging. Electrophysiological studies of the channel indicated that all these missense mutations resulted in loss of function, and the reduction in the potassium-channel current was remedied by the application of the phospholipase inhibitor ONO-RS-082.

CONCLUSIONS

Our study identified the association of a novel gene, KCNK3, with familial and idiopathic pulmonary arterial hypertension. Mutations in this gene produced reduced potassium-channel current, which was successfully remedied by pharmacologic manipulation.

Source: NEJM

 

Genetic advance in Down’s syndrom.

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US scientists say they have moved a step closer to being able to treat disorders caused by an extra chromosome.

They have “switched off” the chromosome that causes the symptoms of Down’s syndrome in human cells in the lab.

The research, published in Nature, could one day lead to new medical treatments for the condition.

Future work may be of real benefit to people with Down’s syndrome, said the UK Down’s Syndrome Association.

Humans are born with 23 pairs of chromosomes, including two sex chromosomes, making a total of 46 in each cell.

People with Down’s syndrome have three – rather than two – copies of chromosome 21.

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 “Start Quote

This is an exciting breakthrough, but this process is still at a very early [cellular] stage and we are nowhere near seeing this procedure being used in the treatment of Down’s syndrome in people”

Dr Lucy RaymondUniversity of Cambridge

This causes symptoms such as learning disabilities and early-onset Alzheimer’s disease, as well as a greater risk of blood disorders and heart defects.

Gene therapy, which uses genes to treat illnesses, has been attempted for problems caused by a single defective gene. But until now, the idea of being able to silence the effects of a whole chromosome had appeared beyond the realms of possibility, even in the lab.

Now scientists at the University of Massachusetts Medical School have shown that, in theory, this might be possible but would take decades of research.

A team led by Dr Jeanne Lawrence inserted a gene called XIST into the stem cells of a person with Down’s syndrome grown in the lab.

‘Exciting research’

The gene plays a role in normal cell development by switching off one of the two X chromosomes present in female embryos, ensuring daughters avoid a double dose of X chromosome genes.

The experiments showed that the gene was able to silence the extra copy of chromosome 21, helping correct unusual patterns of growth in the cells.

Dr Lawrence told BBC News: “The research means that we have a new way – right away – to study the cellular basis for Down’s syndrome, that could help identify drugs for Down’s syndrome.

“At the same time we have made it conceivable – not necessarily possible or effective, that still needs to be proven – but conceivable that you could use just a single gene to correct the over-expression of the whole chromosome. So it makes genetic therapy for Down’s syndrome more conceivable where it really wasn’t before.”

Commenting on the study, Carol Boys, chief executive of the Down’s Syndrome Association, said it was exciting new research from a very well-respected team.

“The findings could have serious implications for future work that may be of real benefit to people with Down’s syndrome,” she said.

“We are a very long way from understanding how these findings might translate into clinical applications but it could be that they will be of great assistance in the search for conventional treatments for some of the health conditions that affect people with Down’s syndrome.”

Dr Lucy Raymond, from the department of medical genetics at the University of Cambridge, said the group had demonstrated an important proof of concept.

“This is an exciting breakthrough, but this process is still at a very early [cellular] stage and we are nowhere near seeing this procedure being used in the treatment of Down’s syndrome in people.”

Source: BBC

Rare Gene Mutations Suggest One More Path to Obesity.

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New research suggests that people with rare mutations of a gene linked with regulating metabolism may be highly susceptible to becoming obese.

The gene involved is known as Mrap2 in mice and as MRAP2in humans. It’s expressed predominantly in the brain, in some of the regions that regulate energy balance. The gene encodes a protein that apparently is linked with increasing metabolism and decreasing appetite.

7-18-13-mice-obesity

To examine the gene’s effect on weight gain, researchers at Boston Children’s Hospital first inactivated Mrap2 in mice. The mice appeared normal until they were about a month old. Then they started to gain more weight, became excessively hungry, and ate more than their siblings with Mrap2 intact.

Even when their food was restricted to the same amount as their normal siblings, mice with the inactivated gene still gained more weight. They didn’t gain weight at the same rate as their siblings until they ate 10% to 15% less food. Mice with both copies of Mrap2 inactivated gained the most weight, but even mice with 1 working copy of the gene gained more weight and had bigger appetites than the normal mice.

When allowed to eat freely, mice with the inactivated gene ate almost twice as much as their siblings. They had more visceral fat, which surrounds organs deep in the abdomen and is linked with cardiovascular disease, diabetes, and colorectal cancer. They also had more fat in their liver, according to the results published online today in the journal Science

“These mice aren’t burning the fat; they’re somehow holding on to it,” the study’s lead investigator, Joseph Majzoub, MD, said in a statement.

Majzoub, chief of endocrinology at Boston Children’s, noted that he and his collaborators found similar mutations in obese participants in the Genetics of Obesity Study, an international effort to determine why some people become severely obese at a young age. They found 4 rare MRAP2 mutations in 500 obese study participants, all who had 1 working copy of the gene.

Rare MRAP2 mutations lead to obesity in fewer than 1% of people with such severe weight problems, the researchers said. But they suspect that other, more common mutations occur in the gene and may interact with various genetic and environmental factors to cause more widespread forms of obesity. They plan to expand the scope of their research to examine that possibility.

Source: http://newsatjama.jama.com