Mutation

Girl who feels no pain could inspire new painkillers.

Posted by

0


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.

dn24196-1_300

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

These Foods Will Help You Live Longer.

Posted by

0


Do you follow a lifestyle that helps you age slower, and promotes longevity? If you aren’t, you should think about starting! These foods can actually enhance your longevity and make you feel healthier, stronger and younger. They have the potential to slow biological aging by providing antioxidants, minerals, vitamins, and an array of other nutrients that help enhance our immune system, combat inflammation, and defend against free radicals.

Berries
Berries are loaded with antioxidants which rapidly slow down the aging process by preventing the damage done by free radicals. A variety of studies have shown that berries, one of the most antioxidant rich fruits, have the ability to improve our memory and keep our brains sharp as we age – say goodbye to dementia and Alzheimer’s!

Water
A large majority of the population is not getting enough water, but drinking water is one of the key elements to increasing your longevity. Drinking at least 2 litres of water daily will help improve your cellular function, metabolism, and organ function. Our bodies are made up of about 60-70% water, so this substance is incredibly essential to proper health!

Broccoli
Raw broccoli is incredibly high in sulforaphane (especially broccoli sprouts). This substance has been found to be very effective in preventing cancer which is one of the main causes of age-related death today (via DNA mutations which naturally occur with age). Broccoli is also loaded with other antioxidants to help protect healthy cells from damage caused by free radicals, leaving us feeling and looking youthful!

Kale
Kale is a cruciferous vegetable, like broccoli, and thus makes it a wonderful cancer-fighting vegetable that you should be including in your diet at least 3 times a week. It clears out free radicals in the body, and contains a ridiculous amount of nutrients like vitamin K (key regulator of inflammation), vitamin C, iron and calcium which are crucial for prolonging our life span.

Thyme
Once upon a time, thyme was used as a preservative in the Mediterranean due to it’s amazing antioxidant properties – in fact, Egyptians once used it for embalming bodies. It’s principal oil called thymol has antibacterial and anti-fungal properties which neutralize disease-causing pathogens such as E.coli and staphylococcus.

Basil
Basil is known for it’s anti-inflammatory properties – inflammation leads to a variety of diseases and illness if left untreated for long periods of time. The better you feel, the better your body and mind function. Particularly, holy basil has been coined the term “the elixir of life,” having the ability to improve human health and longevity. It has been used extensively in Ayurvedic medicine for thousands of years.

Sweet Potato
Sweet potato is wonderful for keeping your hormones in check, as well as boosting your immune system and strengthening your cardiovascular system. They are also rich in vitamin A, B6 and potassium which are linked to excellent heart health, especially with their ability to help regulate blood sugar. Include sweet potatoes in your diet, raw or cooked (yes, sweet potatoes are lovely eaten raw, and are not harmful – shred them in salads!).

Asparagus
Asparagus is loaded with beneficial nutrients which can help us live a long and healthy life. It is a natural detoxifier and diuretic making it effective in preventing kidney stones and urinary tract infections (UTIs). The nutrients in asparagus range from vitamins A, C, B and K, as well as manganese, iron, fibre and folate. It helps promote good digestion, strong bones and a healthy heart, and contains antioxidants like glutathione which is the body’s strongest antioxidant!

Avocado
Avocados are filled with heart-healthy oleic acid which helps lower LDL (“bad”) cholesterol. They are also high in potassium which protects or heart and reduces the risk of developing high blood pressure or suffering from a stroke. They contain folate, and a handful of antioxidants which fight off free radicals, protecting our organs and tissues from damage over time!

Garlic
Garlic is definitely a power food! It contains sulfur compounds which protect our cardiovascular system and prevents heart attacks and stroke. Garlic is also incredibly useful in strengthening our immune system and fighting off free radicals which naturally lead to diseases like cancer and other illnesses.

Source: Live Love Fruit

Molecular Remissions in Myeloproliferative Neoplasms with Pegylated Interferon.

Posted by

0


 

Patients who failed to achieve complete molecular response tended to have mutations in genes outside the JAK2 pathway.
Myeloproliferative neoplasms are a heterogeneous group of diseases most often represented by polycythemia vera (PV) and essential thrombocythemia (ET). Mutations in the JAK2 tyrosine kinase are observed in nearly all patients with PV and in half of those with ET. Treatment with pegylated interferon α-2a (PEG-IFN) has induced complete hematologic and molecular responses and decreased the JAK2V617F allele burden in some but not all patients.

To determine whether patients unresponsive to PEG-INF have mutations in genes lying outside the JAK2 pathway, investigators performed a follow-up of a phase II study of 83 patients (43 with PV and 39 with ET) treated with PEG-IFN (90 µg subcutaneously weekly).

The rate of complete hematologic response was 76% for PV and 77% for ET, and the median time to a complete response was 40 days (range, 3–1478 days). Complete and partial (≥50%) elimination of the JAK2 mutant allele occurred in 18% and 35% of PV patients and 17% and 33% of ET patients, respectively. Patients who failed to achieve complete molecular response tended to have mutant genes outside the JAK2 pathway (56% vs. 30%), but this difference was not significant. However, 9 of 14 who failed to achieve complete molecular response had evidence of clonal evolution of their disease based on the appearance of new genetic abnormalities, whereas none of the 9 patients who achieved complete molecular response acquired new abnormalities. The JAK2burden was higher in patients with a concomitant mutation in TET2 than in those without this mutation (67% vs. 39%; P=0.04), and patients with the TET2 variant did not have a significant decline in the JAK2 mutant allele with PEG-IFN treatment.

COMMENT

Symptomatic patients with polycythemia vera or essential thrombocythemia are usually treated with cytoreductive agents, but these drugs are unsuitable for younger patients, and responses are usually transient. However, if patients can tolerate pegylated interferon α-2a, remission is often sustained. Refractory patients usually have several genetic mutants, and clonal evolution frequently occurs during treatment. The development of new agents targeting mutant genes outside the JAK2pathway should increase the response rate in patients with these myeloproliferative neoplasms.

Source: NEJM

Gene mutation may contribute to body weight regulation, obesity.

Posted by

0


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.

Posted by

0


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

 

Rare Gene Mutations Suggest One More Path to Obesity.

Posted by

0


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

 

Why is cancer so common?.

Posted by

0


_67476237_cancersb10067350d

Hundreds of thousands of people are diagnosed with cancer every year in the UK. It is not one disease; there are over 200 different types, each with its own symptoms, methods of diagnosis and treatment.

What is cancer?

Cancer starts when cells in our bodies start to reproduce out of control, forming new, abnormal cells. These abnormal cells form lumps, known as tumours.

If the cells from tumours cannot spread, then the tumours are benign. They are not cancerous and can usually be removed.

If the cells are able to invade nearby healthy tissue and organs, or spread around the body through the blood or lymphatic system causing further tumours to grow, then the tumours are malignant or cancerous. These cancer cells are likely to spread if the tumour is not treated.

What causes cancer?

Every cell in our body contains DNA. It carries our genetic code and contains the instructions for all the cell’s actions.

If the DNA inside cells is damaged, these instructions go wrong. In fact damage to the DNA or “mutations” as they are known, constantly occur in our cells as they divide and reproduce. Most of the time, the cells recognise that a mutation has occurred and repair the DNA, or self-destruct and die.

When a number of mutations have occurred in the DNA of a cell, control of cell growth may be lost and the cells do not die. Instead they start to follow abnormal instructions that make them reproduce and grow, producing more and more of these mutated cells – this is the start of a cancer.

Many factors such as smoking or too much exposure to the sun can also trigger DNA damage – leading to a faster accumulation of the mutations which lead to cancer.

A family history of cancer can also increase chances of getting the disease, because it usually means that person starts their life already having inherited some of the DNA mutations that take them down the path to cancer.

Even when in remission, those who have had the disease have a higher risk of it developing again. In most cases however, the exact cause or sequence of events by which cancer develops, is not yet known

A recent study has found that there are more than 80 genetic markers (i.e. mutated genes) that can increase the risk of developing breast, prostate or ovarian cancer, for example. Scientists believe the results could soon lead to widespread use of DNA profiling for these cancers, though individual genetic testing for those likely to be at increased risk – such as when there is a strong family history of a type of cancer – is already in use.

Why is it so deadly?

Cancer cells are able to invade other parts of the body, where they settle and grow to form new tumours known as secondary deposits – the original site is known as the primary tumour. The cells spread by getting into the blood or lymph vessels and travelling around the body.

For example, if bowel cancer has spread through the wall of the bowel itself, it can start growing on the bladder. If cells enter the bloodstream they can travel to distant organs, such as the lungs or brain. Over time, the tumours will then replace normal tissue.

The process of cancer cells spreading is called metastasis. Once a cancer has started to spread, the chances of a cure often begin to fall, as it becomes more difficult to treat for a variety of reasons.

Cancer harms the body in a number of ways. The size of the tumour can interfere with nearby organs or ducts that carry important chemicals. For example, a tumour on the pancreas can grow to block the bile duct, leading to the patient developing obstructive jaundice. A brain tumour can push on important parts of the brain, causing blackouts, fits and other serious health problems. There may also be more widespread problems such as loss of appetite and increased energy use with loss of weight, or changes in the body’s clotting system leading to deep vein thrombosis.

Why is it so hard to stop?

Cancer is an extremely complex condition. Each type of cancer is biologically different from any other type. For example, skin cancer is biologically different from the blood cancer called lymphoma, of which there are then many different types.

That is then coupled with genetic differences between individuals and the often random nature of the DNA mutations that cause cancer.

All this makes it difficult to identify the way the particular cancer cells are behaving and how they are likely to spread or damage the body. Without a full understanding of the physiology of the cancer, effective treatments are hard to develop.

How common is cancer?

  • More than one in three people will develop some form of cancer during their lifetime
  • In 2010 324,579 people in the UK were diagnosed with cancer (excluding non-melanoma skin cancer).

Source: Cancer Research UK

Early surgery to remove tumours can work. But the cancer can return if any cells are left behind. It can also return if cells have broken away from the primary tumour and formed microscopic secondary tumours elsewhere in the body before an operation to remove the primary.

And because cancer cells are our own body’s cells, many treatments to destroy them also risk destroying our healthy cells.

One controversial theory of why cancer is so hard to stop is that it is rooted in the ancient traits of our genes.

Prof Paul Davies from Arizona State University believes cancer may use tried-and-tested genetic pathways going back a billion years to the dawn of multicellular life, when unregulated cell growth would have been an advantage.

He argues that this tendency was suppressed by later, more sophisticated genes, but lies dormant in all living organisms. Cancer occurs when something unlocks these ancient pathways.

Other scientists disagree, saying that these pathways would not have survived millions of years of evolution.

One thing is for sure – our genes hold the key to understanding cancer and how to treat it.

The future of cancer research

The field of cancer research is moving away from defining a cancer by where it is in the body, as one type of breast cancer can have more in common with an ovarian cancer than another cancer in the breast.

Instead scientists are looking deeper at what is going wrong inside cancerous cells – a tumour can have 100,000 genetic mutations and these alter over time.

By pinpointing the mutations that can cause certain cancers, doctors hope to personalise treatment – choosing the drug most likely to work on a particular type of tumour.

Scientists are creating targeted cancer therapies using their latest insights into cancer at a molecular level. These treatments block the growth of cancer by interfering with genetic switches and molecules specifically involved in tumour growth and progression.

Clinical trials using gene therapy are also underway. This experimental treatment involves adding genetic material into a person’s cells to fight or prevent disease.

Source: BBC

 

 

Sturge–Weber Syndrome and Port-Wine Stains Caused by Somatic Mutation in GNAQ.

Posted by

0


BACKGROUND

The Sturge–Weber syndrome is a sporadic congenital neurocutaneous disorder characterized by a port-wine stain affecting the skin in the distribution of the ophthalmic branch of the trigeminal nerve, abnormal capillary venous vessels in the leptomeninges of the brain and choroid, glaucoma, seizures, stroke, and intellectual disability. It has been hypothesized that somatic mosaic mutations disrupting vascular development cause both the Sturge–Weber syndrome and port-wine stains, and the severity and extent of presentation are determined by the developmental time point at which the mutations occurred. To date, no such mutation has been identified.

METHODS

We performed whole-genome sequencing of DNA from paired samples of visibly affected and normal tissue from 3 persons with the Sturge–Weber syndrome. We tested for the presence of a somatic mosaic mutation in 97 samples from 50 persons with the Sturge–Weber syndrome, a port-wine stain, or neither (controls), using amplicon sequencing and SNaPshot assays, and investigated the effects of the mutation on downstream signaling, using phosphorylation-specific antibodies for relevant effectors and a luciferase reporter assay.

RESULTS

We identified a nonsynonymous single-nucleotide variant (c.548G→A, p.Arg183Gln) in GNAQ in samples of affected tissue from 88% of the participants (23 of 26) with the Sturge–Weber syndrome and from 92% of the participants (12 of 13) with apparently nonsyndromic port-wine stains, but not in any of the samples of affected tissue from 4 participants with an unrelated cerebrovascular malformation or in any of the samples from the 6 controls. The prevalence of the mutant allele in affected tissues ranged from 1.0 to 18.1%. Extracellular signal-regulated kinase activity was modestly increased during transgenic expression of mutant Gαq.

CONCLUSIONS

The Sturge–Weber syndrome and port-wine stains are caused by a somatic activating mutation in GNAQ. This finding confirms a long-standing hypothesis.

 

Source: NEJM

 

 

 

 

 

MAP kinase signaling and inhibition in melanoma..

Posted by

0


The mitogen-activated protein kinase (MAPK) pathway is critical to oncogenic signaling in the majority of patients with malignant melanoma. Driver mutations in both NRAS and BRAF have important implications for prognosis and treatment. The development of inhibitors to mediators of the MAPK pathway, including those to CRAF, BRAF, and MEK, has led to major advances in the treatment of patients with melanoma. In particular, the selective BRAF inhibitor vemurafenib has been shown to improve overall survival in patients with tumors harboring BRAF mutations. However, the duration of benefit is limited in many patients and highlights the need for understanding the limitations of therapy in order to devise more effective strategies. MEK inhibitors have proven to particularly active in BRAF mutant melanomas also. Emerging knowledge about mechanisms of resistance as well as a more complete understanding of the biology of MAPK pathway signaling provides insight into rational combination regimens and sequences of molecularly targeted therapies.

Source: Oncozene

 

New Syndrome of Paraganglioma and Somatostatinoma Associated With Polycythemia .

Posted by

0


Abstract

Purpose The occurrence of ≥ two distinct types of tumors, one of them paraganglioma (PGL), is unusual in an individual patient, except in hereditary cancer syndromes.

Patients and Methods Four unrelated patients were investigated, with thorough clinical evaluation. Plasma and tissue catecholamines and metanephrines were measured by high-performance liquid chromatography. Anatomic and functional imaging were performed for tumor visualization. Germline and tumor tissue DNA were analyzed for hypoxia-inducible factor 2 alpha (HIF2A) mutations. The prolyl hydroxylation and stability of the mutant HIF2α protein, transcriptional activity of mutant HIF2A, and expression of hypoxia-related genes were also investigated. Immunohistochemical staining for HIF1/2α was performed on formalin-fixed, paraffin-embedded tumor tissue.

Results Patients were found to have polycythemia, multiple PGLs, and duodenal somatostatinomas by imaging or biochemistry with somatic gain-of-function HIF2Amutations. Each patient carried an identical unique mutation in both types of tumors but not in germline DNA. The HIF2A mutations in these patients were clustered adjacent to an oxygen-sensing proline residue, affecting HIF2α interaction with the prolyl hydroxylase domain 2–containing protein, decreasing the hydroxylation of HIF2α, and reducing HIF2α affinity for the von Hippel–Lindau protein and its degradation. An increase in the half-life of HIF2α was associated with upregulation of the hypoxia-related genes EPO, VEGFA, GLUT1, and END1 in tumors.

Conclusion Our findings indicate the existence of a new syndrome with multiple PGLs and somatostatinomas associated with polycythemia. This new syndrome results from somatic gain-of-function HIF2A mutations, which cause an upregulation of hypoxia-related genes, including EPO and genes important in cancer biology.

 

Source: JCO