Tangier Disease Lipid Disorder Biology Essay
Tangier disease (TD) is an autosomal recessive inherited disease which causes Lipid disorder. This rare disease is also known as "Familial alpha -lipoprotein deficiency"1.The disease is caused by the deflected ABCA1 gene (ATP-binding cassette A )which is originally responsible for cholesterol transport. The deflected gene will cause the severe reduction of high density lipoprotein (HDL) in the bloodstream by inhibiting the function of ATP-binding cassette transporter.
This disease is first found on a little boy living on the Tangier Island. In 1988, there are 27 cases had been reported? In 1992 there are still less than 50 patients suffer from TD reported worldwide. TD is a genetical disease, the majority of this disease is in the Tangier island , Virginia in U.S.A .Data show that people who suffer from this genetic disorder live close to each other , this could be explained by the Founder's effect. Until now there are only about 100 cases identified worldwide and some cases are still undiagnosed. The prevalent is about 1:120000000 in U.S.A (National institute of health).
Sign and symptom
People suffer from Tangier Disease will present with orange and enlarged tonsils . This is always the first symptom. They will have Enlarged spleen, Enlarged liver , Cloudy cornea and Early-onset cardiovascular disease. They will also show ployneuropathic symptom and sign.
The accumulation of cholesterol in the artery wall cell will initiate atherosclerotic cardiovascular disease. Also accumulation in eye will lead to Retinitis Pigmentosa. It leads to ploy- neuropathy. Moreover, HDL deficiency syndrome is caused by the rapid degradation of apoA-I
What is HDL
High-density lipoprotein (HDL) is the smallest but it has the highest proportion of protein within the five major groups of lipoproteins. It consists of large amount of apolipoprotein (apo-I and ApoA- II) which produce by the liver. The free cholesterol will be converted to cholesteryl ester by lecithin-cholesterol acyltransferase which is a plasma enzyme. A new HDL will then produced by the bind of the cholesteryl ester to the core of the lipoprotein. Moreover The HLD is able to interact with the ABCG1 transporter to pick up cholesterol. In fact, the HDL will increase its size when binding with more cholesterol throughout the blood circulation system. The function of HDL is generally helping hydrophobic compound e.g. cholesterol to travel in the hydrophilic blood circulation system. In addition, there are 30% blood cholesterol carried by HDL within a healthy person.
"The Tangier disesease is cause by homozygosity for a dinucleotide deletion in exon 22 of the ABCG1 gene which is on the chromosome 9q22-q31. "The ABCA1 gene codes for protein ABCA protein with 2262 amino acid which able to form a ATP-binding cassette transporters (ABCA1). The mapping of this gene is done in 1998 and it shows that the deletion of the 9q22-q31 will cause the reduce level of HDL. The ABCA protein a major protein that is needed to form a important transporter knows as ATP- binding cassette transporter (ABCA transporter) . The ABCA transporter is a transmembrane protein . By the hydrolysis of ATP to ADP, energy is provided for the transporter which allows the translocation excess free - cholesterol and phospholipids across the cell membrane into the HDL metabolic pathway . This is due to the cholesterol homeostasis of the cell. In fact, apart from liver and steroidogenic tissues, other cell are not able to metabolize cholesterol . In addition, the transporter also provided other non-transport-related process.
The deflected(mutated) ABCG1 genes cause the abnormal function of a ATP-binding cassette transporters. This abnormality does not allow the transporter effectively efflux cholesterol and other lipid out of the cell. In a normal condition the ABCG1 is able to let cholesterol exit from the cell. The exited free cholesterol is then able to bind with Apo-A1 lipoprotein to form HDL . The HDL will pick up the low density Lipoprotein (LDL) and very low density Lipoprotein (VLDL), which can known as bad cholesterol, throughout the blood vessels and transport the cholesterol back to the live for excretion or re-utilization. In this process, cholesterol from arteries is removed .This could increase the protection against cardiovascular diseases. However, patient suffer from TD will accumulate the cholesterol within the tissue which is toxic and will cause pathological consequence to the cell of artery wall. In addition, there is no or really little free cholesterol transport out of the cell , as a result Low HDL and LDL level and higher amount of fat in the circulation system. This could bring a great increase in risk of atherosclerosis.
TD is a autosomal recessive disease. This means the patient suffer from TD must have two copies of the abnormal genes (recessive homozygotes). If the disease of the patient passes down through families, this means that the parent of the patient must be a carrier (with one normal and one defective gene) or suffer from TD. In some research it shows that although TD is a caused by homozygote recessive, the HDL still shows one-half lower than the normal in the heterozygous condition.
Nowadays there is no a specific treatment of drugs that could completely cure the Tangier disease. This is because TD is a genetical disease which affect all the cell in the body and disrupt the lipid metabolic pathway. We know that TD causes the decrease of HDL, however the medication using to treat decrease HDL is ineffective. On the other hand, some treatment is used to reduce the impact causing by other disease trigger by TD. When the there is excess accumulation of cholesterol in the organ such as spleen and tonsils, then those organ will be removed. Arteriosclerosis and Coronary artery disease can be treated angioplasty and by bypass surgery. In the angioplasty , a small hollow tube with a deflated balloon is inserted from the arm to the artery where clogged happened. By inflating the balloon which is able to enlarge the artery and compress the blockage. Unfortunately, TD is continuously increase the risk of cardiovascular disease, so usually these treatment for acute condition.
Understanding of other disease when researching in to tangier disease.
When researching into tangier disease , it show that plasma HDL has a great inverse relationship to the risk of cardiovascular disease. The research also implies that HDL give a protection to against atherosclerosis. In some research also the over expression of ABCA1 on a mouse reduce atherosclerotic lesions due to increase amount of HDL. On the other hand, as tangier disease patient show the defect of ABCA1 transporter which then bring out a lot of other disease . This could clear means that all different transporter, enzyme etc. have their important role of regulating of metabolic pathway . In addition, HDL also shows that metabolic substance in correct amount is needed to maintain the body in a healthy way.
TD as a genetic disease shows a good example of understanding other genetic disease. The Mutation of Gene (DNA sequences changed) is transcribed and translated. a new protein is synthesized instead of the original one , this may cause the deflect of the function group e.g. enzyme , transporter. If the deflected gene affects the function group will cause other metabolic disease e.g. DIDMOAD syndrome, glucose 6-phosphage dehydrogenase (G6PD) deficiency etc. This is due to the metabolic pathway is being disrupted.
As the metabolic pathways are being disrupted, this will then cause a lot of different metabolic substance deficiency and excess inside the body. Moreover, some of the metabolic substance as a role of being a signaling molecules which is important. In order to complete cure of these disease gene therapy is needed. However this therapy is still under investigating.
For a genetic disease, mapping allows us to which gene is mutated. In the other way of thinking, it means we are able to allocate which part of gene on the chromosome is response for what function.
By the research on this disease, ABCA1 transport is important to control the incident rate of the cardiovascular disease which is caused by the blockage of artery.
TD is a rare inhered genetic disease; the research of this disease is related to the research in lipoprotein and cardiovascular disease. This disease shows that the significant of the ABCA1 transporter in regulation of the lipid metabolism. The great decrease of the HLD in blood circulation system and accumulation of cholesterol in cell, give evidence that the ABCA1 transporter is the major efflux of excess cholesterol from cell for homeostasis. In the future, the explore of more genetic finger printing and the develop of gene therapy could allow us to cures this genetic disease . Moreover, it also allow us to have fully understand about different disorder ,in order to give the best therapy to the patient.
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