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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Gene mutation linked with liver cancer

Presently, there is no effective treatment for the cancer found in the liver called fibrolamellar hepatocellular carcinoma, which is mainly found among children and young people. Operation of the tumour is the only treatment, some of the patients do not survive after five years.

Coupling of the two genes through a mutation causes a cancer tumour to develop in the liver. The researchers have made sure the genetic composition of the mutation in the mice is identical with the mutation found in human patients. This makes the researchers conclude that the gene mutation also leads to cancer in humans.

Sequencing the DNA of the patients tumour showed that all the patients suffering from the disease had the same mutation in their DNA. The researchers used the revolutionary technology CRISPR/Cas9 that makes it possible to 'edit' genetic material on mice.
They have produced CRISPR/Cas9 reagents, which would provoke precisely the desired fusion of the two genes.

The reagents were injected into the mice's tails and then transported through the bloodstream to the liver.
 In the liver they created a mutation identical with the human mutation, then the researchers were able to conclude that the mice developed the expected type of tumour in the liver.

In other studies, researchers deliberately damage the mice's liver to imitate a liver disease found among human patients or expose them to several different forms of mutations which may cause cancer. This was not necessary here. Because of our genetic design based on CRISPR/Cas9-technology we are certain that the main factor that can explain the cancer is the fusion of the two genes.

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Children of older women may develop cancer

Increase in chromosomal mutations as we get older may increase the risk of giving birth to children that will develop cancer, acute lymphoblastic leukemia and non-Hodgkin lymphoma.

Increasing chromosomal aberrations with older parental may cause stillbirth or a baby with conditions like autism and Down’s syndrome.

A chromosome mutation is an unpredictable change that occurs in a
chromosome. This change is caused by problems that occur during cell division process.

Increasing new mutations that happens in sperm or egg cells are associated with the parents age. These increases the risk of birth defects related to single gene mutations and neurodevelopmental disorders.

Older parents can reduce the risk by embracing healthy lifestyle, reducing alcohol intake, avoiding smoking and chemical exposure.
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Gene mutation can leads to brain malformation

Gene controls nerve stem cell growth and how it causes abnormal brain development in fetuses if the system goes wrong. Researchers explained how Dmrta2 controls gene in the division of cells and the production of specialised cells.

If Dmrta2 gene mutation is inherited from parents, it can cause brain malformations known as lissencephaly. Lissencephaly is a nervous system disorder in which a baby's brain is not fully developed.

Lissencephaly occurs in the second trimester of pregnancy, and leaves the fetus with a small brain and it prevents the development of brain folds and grooves which are needed for language skills and learning.

Researchers genetically mutated the Dmrta2 gene in embryonic stem cells to check the impact of too much or too little protein levels on brain development.

 They examined the effect of these changes on laboratory-created nerve cells, it shows a direct link between Dmrta2 mutation and the microcephaly.

When Dmrta2 gene is not maintaining balance between neurogenesis and cell cycle progression, brain development is altered. This can cause neurodevelopmental condition like autism.
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