How gene mutation triggers the immune system

Scientists discovered how a gene mutation affects T cell function to promote immune disorders and then tested a treatment based on the discovery-successfully fixing donated immune cells from a 16-year-old boy with an abnormally low level of white blood cells called lymphopenia. The discovery centers on mutation of the gene Gimap5, which is important to the healthy formation and function of CD4+ T cells, one of the immune system's super soldiers against infection and disease.

The protein associated with the Gimap5 gene (also Gimap5), is important because it regulates a protein that inactivates an enzyme called GSK3, researchers said. If GSK3 isn't inactivated it causes DNA damage in T cells that are expanding, causing the cells not to survive or function properly. In mice and human blood cells, the researchers tested drugs that inhibit GSK3, improving immune system function in mice and restoring normal T cell function in the human cells.

GSK3 inhibitors are used to treat other diseases like Alzheimer's, mood disorders and diabetes mellitus. GSK3 inhibitors will improve T cell survival and function and may prevent or correct immune-related disorders in people with Gimap5 loss-of-function mutations.Therapeutically targeting this pathway may be relevant for treating people with Gimap5 mutations linked to autoimmunity in Type 1 diabetes, systemic lupus erythematosus or asthma.

Hoebe led the study, together with Andrew Patterson, a PhD student in Hoebe's lab, and Jack Bleesing, MD, PhD, in the Division of Bone Marrow Transplantation and Immune Deficiency. Immune system disorders lead to abnormally low immune activity (deficiency) or overactivity (autoimmunity). Immune deficiency diseases decrease the body's ability to fight infection, while autoimmunity prompts the body to attack its own tissues. Both are common causes of illness, and malfunctioning T cells are linked to both.

The Gimap5 gene controls its associated protein Gimap5 (GTPase of immunity associated protein 5). As the name suggests, its role is mainly linked to immune system function, lymphocyte white blood cell survival and T cell formation in the thymus. Genetic variants in Gimap5 were already associated with autoimmunity and colitis.
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Roles of brain protein

A protein called AKT, is ubiquitous in brain tissue and instrumental in enabling the brain to adapt to new experiences and lay down new memories. AKT comes in three distinct varieties residing in different kinds of brain cells and affecting brain health in very distinct ways. It is a central protein that has been implicated in a bevy of neurological diseases.

Discovered in the 1970s and known best as an "oncogene" (one that, when mutated, can promote cancer), AKT has more recently been identified as a key player in promoting "synaptic plasticity," the brain's ability to strengthen cellular connections in response to experience. AKT is one of the first proteins to come up after observing scary objects, it is a central switch that turns on the memory factory.

For the study, Hoeffer's team silenced the three different isoforms, or varieties, of AKT in mice and observed their brain activity. They made a number of key discoveries: AKT2 is found exclusively in astroglia, the supportive, star-shaped cells in the brain and spinal cord that are often impacted in brain cancer and brain injury.

 AKT1 is ubiquitous in neurons and appears to be the most important form in promoting the strengthening of synapses in response to experience-memory formation. (This finding is in line with previous research showing that mutations in AKT1 boost risk of schizophrenia and other brain disorders associated with a flaw in the way a patient perceives or remembers experiences.)
AKT3 appears to play a key role in brain growth, with mice whose AKT3 gene is silenced showing smaller brain size.
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Luxturna for treating inherited retinal disease

Luxturna (voretigene neparvovec) is an adeno-associated viral (AAV) vector gene therapy for the treatment of patients with vision loss due to confirmed biallelic RPE65-mediated inherited retinal disease (IRD). Luxturna is approved for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy that leads to vision loss and may cause complete blindness in certain patients.

Hereditary retinal dystrophies are a broad group of genetic retinal disorders that are associated with progressive visual dysfunction and are caused by mutations in any one of more than 220 different genes. Biallelic mutation carriers have a mutation (not necessarily the same mutation) in both copies of a particular gene (a paternal and a maternal mutation). The RPE65 gene provides instructions for making an enzyme (a protein that facilitates chemical reactions) that is essential for normal vision.

 Mutations in the RPE65 gene lead to reduced or absent levels of RPE65 activity, blocking the visual cycle and resulting in impaired vision. Individuals with biallelic RPE65 mutation-associated retinal dystrophy experience progressive deterioration of vision over time. This loss of vision, often during childhood or adolescence, ultimately progresses to complete blindness.

Luxturna works by delivering a normal copy of the RPE65 gene directly to retinal cells. These retinal cells then produce the normal protein that converts light to an electrical signal in the retina to restore patient’s vision loss. Luxturna uses a naturally occurring adeno-associated virus, which has been modified using recombinant DNA techniques, as a vehicle to deliver the normal human RPE65 gene to the retinal cells to restore vision. Luxturna should be given only to patients who have viable retinal cells as determined by the treating physician(s).

 Treatment with Luxturna must be done separately in each eye on separate days, with at least six days between surgical procedures. It is administered via subretinal injection by a surgeon experienced in performing intraocular surgery. Patients should be treated with a short course of oral prednisone to limit the potential immune reaction to Luxturna. The most common adverse reactions from treatment with Luxturna included eye redness (conjunctival hyperemia), cataract, increased intraocular pressure and retinal tear.
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Breast cancer gene

Breast cancer is caused by complex interactions between a large number of genetic variants and our environment. The inherited component of breast cancer risk is due to a combination of rare variants in genes such as BRCA1 and BRCA2 that confer a high risk of the disease, and many genetic variants that each confer only a small risk.

The newly identified risk regions nearly double the number that are already known, thereby bringing the number of known common variants associated with breast cancer to about 180.
One in five women are in greater danger of getting breast cancer because of faults in their genes. Women are at risk of breast cancer if their mother, daughter or sister has breast cancer.

For one in five women, the errors written into their genes mean they have almost a third higher chance of getting breast cancer. An unlucky one per cent have three times the risk of the other 99 per cent of the population.

These gene changes now have the potential to be incorporated into existing models to accurately predict an individual's risk, and to improve both prevention and early detection of the disease. The study looked at 11.8 million single-letter 'spelling mistakes' in women's DNA which increase their risk of breast cancer.

The researchers discovered nine more variations affecting the gene BRCA1. In total, they have confirmed 107 genetic variants and discovered 72 new ones. The discovery allowed the team to calculate that one in ten women have a 70 per cent higher risk of getting breast cancer.

About 70 per cent of all breast cancers are fuelled by the sex hormone oestrogen and respond to hormone therapies such as tamoxifen.
Others, known as oestrogen-receptor negative, are not affected by the hormone and are more difficult to treat.

In a second study, the researchers found 10 new variants linked to these cancers, the two cancer types are biologically distinct and develop differently.
Breast cancer susceptibility is due to the effect of a large number of inherited genetic variants, each of which may only confers a slight increase in breast cancer risk, when the strongly predisposing genes such as BRCA1 and BRCA2 are not considered.

The study discovered 65 new variants, some of which are common, have each of which has only a small effect on breast cancer risk, but cumulatively they could be very important in altering a woman's risk of breast cancer.
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Gene controls birth defects common in diabetic patients

Neural tube defects (NTDs) occur when mutations accumulate in the neuroepithelial cells, neural stem cells that eventually transform themselves into the brain and the central nervous system.

This  occurs after the fetus is exposed to too much glucose, which can cause widespread cell death, eventually leading to the birth defects.

Researchers have identified a gene that plays a key role in the formation of neural tube defects, a problem commonly found in infants of pregnant women with diabetes.

Neural tube defects are birth defects of the brain and spinal cord. They occur in the first month of pregnancy. The two most common are spina bifida and anencephaly.

 In the first, the fetal spinal column doesn't close completely. This usually causes nerve damage, with some paralysis of the legs. In the latter, most of the brain and skull do not develop.

 Infants with this defect are usually stillborn or die soon after birth. Neural tube defects have several causes, including diabetes, folic acid deficiency, obesity in the mother, and consumption of certain medications.

About 10 percent of women with diabetes who are pregnant will have embryos with neural tube. More than
300,000 pregnancies are affected by NTDs every year. One out of ten babies with NTDs die before their first birthday.

Pregnant women who have diabetes have a significantly higher risk of having a child with NTDs, and even with the highest quality preconception care, diabetic women are five times more likely to have a child with birth defects than non-diabetic women.

How the body fight viruses

Viruses are  very small infectious agents that reproduce and grow inside the living cells of other organisms.

Researchers from the University of Rochester Center for RNA Biology examined the role of piRNA in protecting the genetic information in germ cells.

piRNA is a type of ribonucleic acid that is in testes and ovaries, piRNA prevents genetic sequences of viral intruders from attacking testes and ovaries.

Defects or Mutations in piRNA can cause infertility in humans and others animals, scientists used rooster testes to test effects of piRNA.

They discovered that chicken harbour a lot of viruses and discovered that host of a virus can turn a virus into a source of strength to fight with other viruses in future.

Scientists discovered that chickens turn the old virus in their body to piRNA- producing machine. This shows that human and animal protect themselves by using old virus to protect themselves from new virus attack.

Scientists discovered cancer-related gene mutation

Cancer starts with production of abnormal cell growth of genetic mutation.

Researchers from University of Maryland led by Thomas Peterson examined similar mutations that are all over genome.

They used genetic data to examined subcomponents of protein domain and discovered that each domain carries out different roles and still share the same protein domain.

Researchers focused on mutations in one region of specific genes and mutations in similar region across families of protein.

Data about somatic variants from 5,848 patients was collected with some patients having 20 different types of cancers.

Detecting variants for tumorigenesis will expose the cause of tumour progression leads to production of drugs for families of genes that shows similar variation at functional level.

Defective HIV proviruses prevent cure

Proteins created by defective forms of HIV associate with immune systems are monitored by cytotoxic T cells.

HIV proviruses are many in HIV patients, the faulty proteins they produce can hinder measurement of viral load, exhaust immune systems and prevent suppression of the virus.

Researchers are trying to hypermutate the proviruses and destroy defective HIV proviruses and develop cure for HIV infection.

Scientists collected defective HIV proviruses from 9 HIV patients and transfected cultures of human immune cells in laboratory.

It was discovered that the transfected human immune cells were capable of making HIV protein despite mutations.

Defective proviruses contribute to viral RNA and protein production and increase the viral load of HIV patients.

Discovery of protein linked to many autoimmune diseases

Researchers have discovered a new method of detecting small amount of a protein known as interferon in patients.
The method shows different levels and cellular sources of diseases.

Interferon are group of signaling proteins made by host cells in response to the presence of many pathogens like virus, bacteria, tumor cells and parasites.

Wrong activation of interferon signal can cause the immune system to attack healthy tissue and cause many autoimmune diseases in the body.

Elevated interferon is associated with complex autoimmune disorder like SLE, dermatomyositis and diabetes.

Mutations in genes can also cause type 1 interferonopathies. Darragh Duffy and some researchers developed an ultra sensitive method of detecting small amount of interferon in human blood.

The researchers were able to measure interferon levels in the blood of healthy SLE, dermatomyositis and type 1 interferonopathy patients.

Interferon levels were high in patients with type 1 interferonopathies, by isolating individual types of blood cells, it was discovered that mutations in a gene known as STING can cause high production of interferon.

Sleeping less than five hours increases risk of prostate cancer

According to scientists, sleeping less than five hours a night may increase the risk of developing prostate cancer.

Men above 65 years that are not sleeping up to seven hours recommended by National Sleep Foundation are at risk of developing terminal diseases.

American Cancer Society in Atlanta examined data from two long-term studies. The first study followed more than 407,000 men between 1950 and 1972, the second followed 416,000 men from 1982 to 2012.

All the men were cancer free at the beginning of the study, more than 1,500 men in first study and more than 8,700 men in second study died of prostate cancer when checked out later.

Not sleeping very well turned off genes that protect cancer growth and prevent production of melatonin. According to Dr Gapstur, reduced melatonin can accelerate genetic mutations, reduced DNA repair and weakened immune system.

Random DNA mistakes causes cancers

Cancer center scientists reported that unpredictable DNA copying errors is responsible for two - thirds of the mutation that cause cancer. This is confirmed by DNA sequencing and epidemiologic data across the globe.

According to professor John Hopkins Kimmel, anytime a normal cell divides to form two new cells, it makes multiple mistakes, these mistakes are source of cancer mutation that have been ignored in the past. This revealed the reasons why people that embraced healthy lifestyle are having cancer.

Researchers studies 32 types of cancers and estimate that 66 percent of cancer mutations occur from coping mistakes, 29 percent from environmental factors and 5 inherited.

Living healthy lifestyle can reduce rates of cancer mutations because mutation can not be stopped from taking place in the body.