Multiple sclerosis (MS) - CYP27B1, HLA-DRB1, IL2RA, IL7R and TNFRSF1A genes
Multiple sclerosis (MS) is an autoimmune disease characterized by lesions in the brain and spinal cord. These lesions are associated with the destruction of the myelin sheath and damage to nerve cells.
Multiple sclerosis usually manifests in early adulthood, between 20 and 40 years old. Symptoms vary widely, and affected people may develop one or more effects of damage to the nervous system. Often, multiple sclerosis causes sensory disturbances in the extremities, including tingling, numbness, pain and itching. Some people manifest sign of Lhermitte, a cramping sensation that runs along the spine and extremities, and usually happens when the head is tilted forward. Problems with muscle control are also common in people with multiple sclerosis, so affected individuals may have tremors, spasticity, hyperreflexia, weakness or partial paralysis of the muscles of the limbs, difficulty walking, or reduced control bladder. Multiple sclerosis is also associated with vision problems, such as blurred or double vision, loss and partial or complete vision. Infections that cause fever can worsen symptoms.
There are several forms of multiple sclerosis: Progressive relapsing-remitting MS, secondary progressive MS, primary progressive MS and relapsing. The most common is relapsing-remitting, so that affects about 80% of people with multiple sclerosis. People with this form of the disease have periods during which symptoms manifest, followed by asymptomatic periods. Triggers episodes and clinical remissions are unknown. After about 10 years, the relapsing-remitting MS usually becomes secondary progressive. In this way, no referrals, and disease symptoms worsen continuously.
Primary progressive MS is the next most common form, affecting approximately 10 to 20% of people with multiple sclerosis. This form is characterized by constant symptoms that worsen over time without episodes or clinical remissions. Primary progressive MS usually starts later than other forms, around 40 years. Progressive relapsing is a rare form of multiple sclerosis which initially appears as primary progressive MS, with constant symptoms. However, people with progressive relapsing also manifest clinical episodes with more severe symptoms.
Although the cause of MS is unknown, it is believed that variations in dozens of genes are involved in the risk of developing multiple sclerosis. Changes in the HLA-DRB1 (major histocompatibility complex, class II, DR beta 1) gene are genetic risk factors most involved in the development of multiple sclerosis. Other factors associated with an increased risk of developing multiple sclerosis include changes in the IL7R (Interleukin 7 receptor) gene and environmental factors such as exposure to Epstein-Barr virus, low concentrations of vitamin D, and smoking.
The HLA-DRB1 (major histocompatibility complex, class II, DR beta 1) gene, located on the short arm of chromosome 6 (6p21.3), belongs to a family of genes called human leukocyte antigen complex (HLA). The HLA complex helps the immune system to distinguish proteins body's own proteins encoded by pathogens such as viruses and bacteria. Each HLA gene has many different normal variations, allowing the immune system reacts to each individual a wide range of foreign proteins. Variations in various HLA genes have been associated with an increased risk for multiple sclerosis but a particular variant of the HLA-DRB1 gene, termed HLA-DRB1 * 15: 01, is the genetic factor associated more frequently. Because the HLA-DRB1 gene is involved in the immune system, changes in it, may be related to the autoimmune response and inflammation damages the nerves and the myelin sheath. However, it is unclear exactly what variants of HLA-DRB1 gene play a role in the development of multiple sclerosis. A combination of genetic and environmental factors is likely involved in this disease.
The IL7R (Interleukin 7 receptor) gene, located on the short arm of chromosome 5 (5p13), encodes the alpha chain of interleukin 7 receptor (IL-7). This protein is a subunit of both the receptor for interleukin 7 (IL-7) receptor as thymic stromal lymphopoietin the (TSLP). Both receptors are embedded in the membrane of immune cells. These receptors stimulate signaling pathways that induce growth, proliferation and survival of immune cells. We have identified a common variation IL7R, Thr244Ile gene that increases the risk of developing multiple sclerosis. This genetic variation results in the encoding of an IL-7 receptor that is not embedded in the cell membrane but is inside the cell. It is not known if this change affects the TSLP receptor. Because the IL7R gene involved in regulation of the immune system, changes in it could be involved in autoimmune response and inflammation damages the nerves and the myelin sheath, leading to the signs and symptoms of multiple sclerosis . However, it is unclear exactly what role the gene variant IL7R in the development of multiple sclerosis. It is likely that a combination of genetic and environmental factors is involved.
Besides variations in HLA-DRB1 and IL7R genes have been associated mutations in the CYP27B1 (cytochrome P450 family 27 subfamily B member 1), IL2RA genes (interleukin 2 receptor subunit alpha) and TNFRSF1A (tumor necrosis factor receptor superfamily member 1A) with the development of multiple sclerosis.
The CYP27B1 (cytochrome P450 family 27 subfamily B member 1) gene, located on the long arm of chromosome 12 (12q14.1), encoding the 1-alpha-hydroxylase enzyme. This enzyme carried out the final reaction to convert vitamin D to its active form, 1,25-dihydroxyvitamin D3, also known as calcitriol. When active, this vitamin is involved in maintaining the proper balance of various minerals in the body, including calcium and phosphate, which are essential for the normal formation of bones and teeth. One of the main functions of vitamin D is the control of calcium and phosphate absorption from the intestines into the bloodstream. Vitamin D is also involved in several processes unrelated to bone formation.
The IL2RA (Interleukin 2 receptor alpha subunit) gene, located on the short arm of chromosome 10 (10p15-p14), encoding the receptor alpha interleukin-2. This receptor is involved in the regulation of immune tolerance by controlling regulatory T cells (Treg). Tregs suppress activation and expansion of autoreactive T cells.
The TNFRSF1A (Tumor necrosis factor receptor superfamily member 1A) gene, located on the short arm of chromosome 12 (12p13.2), encoding the receptor 1 tumor necrosis factor (TNFR1). This protein is found within the cell membrane, where it binds to another protein called tumor necrosis factor (TNF). This connection, sends signals that can trigger the cell initiates inflammation or destruction. Signaling within the cell initiates a route that becomes a protein called nuclear factor kappa B that causes inflammation and leads to encoding immune system proteins called cytokines. Apoptosis is initiated when TNFR1 protein, protein bound to TNF, is located in the cell and triggers a process known as caspase cascade.
The inheritance pattern of multiple sclerosis is unknown, although it seems transmitted from generation to generation in families affected. The risk of developing multiple sclerosis is higher for siblings or children of a person with the disease compared to the general population.
Tests in IVAMI: in IVAMI perform the detection of mutations associated with multiple sclerosis (MS), by complete PCR amplification of the exons of CYP27B1, HLA-DRB1, IL2RA, IL7R and TNFRSF1A genes, respectively, and subsequent sequencing .
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).