User:MayaHines/sandbox

Tangier's Disease
Tangier's disease is a rare autosomal recessive disorder characterized by a severe deficiency in high-density lipoprotein (HDL), resulting in cholesterol esters accumulation in the tissues.

History
Dr. Donald Fredrickson, an American medical researcher, and his colleagues first described Tangier disease. Dr. Fredrickson discovered this disease after traveling to Tangier Island in the Chesapeake Bay and doing research on two young siblings and their family who lived there. Among other symptoms, Dr. Fredrickson noted their moderate hypertriglyceridemia and mild corneal opacification. Fredrickson and colleagues also found that the heterozygote parent's levels of HLH were half of what an individual that was not a carrier would be. They as well discovered that among the family there were cases of neuropathy.

A mutation of the ABCA1 gene on chromosome 9q31 is responsible for Tangier disease. Dr. Assmann, Dr. Rust, and their colleagues first determined the location of this gene in 1998. Following this discovery, Dr. Schmitz and his colleagues discovered the normal function of the ABCA1 gene, which is the role it plays in the efflux of cellular cholesterol and phospholipid on HDL and its components. mjh3w8MayaHines (talk) 05:20, 28 November 2016 (UTC)

Signs and Symptoms
Tangier’s disease is characterized by a severe deficiency of familial high-density lipoprotein (HDL) in the body. Low levels of HDL are accompanied by low levels of apolipoprotein A-I (apoA1), which is a major protein component of HDL in the blood plasma. ApoA1 promotes movement of cholesterol from tissues to the liver for excretion. It also functions as a cofactor for lecithin cholesterolacyltransferase (LCAT), an enzyme responsible for the formation of cholesterol esters. Clinical expressivity of symptoms differs from patient to patient. Diagnosis can take place early on, but is difficult as some affected individuals do not exhibit symptoms. Infected individuals have low levels of HDL and apoA-I (both below 5mg.Dl). These low serum levels of cholesterol cause symptoms including epatosplenomegaly, anemia, thrombocytopenia, and stomatocytoses. The most characteristic symptom observed in infected individuals are enlarges tonsils that are orange-yellow in color. Jndzp5 (talk) 11:15, 1 December 2016 (UTC) This phenotype can be used as a determinant for diagnosing the disease. But not all patients exhibit this symptom. Some adults may have had their tonsils removed, preventing them from having this symptom. Adults have a higher risk of having peripheral neuropathy, which is damage to nerves in the body. This damage usually comes from demyelination and axonal degeneration of the nerve cells. Another common symptom is an accumulation of cholesterol esters in tissues throughout the body. This is caused by the low levesl of apoA-1 as they function as cofactors to LCAT. One of the more severe symptoms is that Tangier's Diseases can lead to cardiovascular disease. This is because HDL functions as a modulator of inflammatory response, antioxidant activity, and vasomotor regulation. For this reason low levels of HDL can lead to cardiovascular disease in Tangier patients. The symptoms of this disease are not guranteed and can vary from each individual, thus making it harder to diasgnose infected individuals. Jndzp5 (talk) 11:16, 1 December 2016 (UTC)

Genetics
Tangier's disease (TD) is an autosomal recessive disorder characterized by a loss of function mutation which occurs in the ATP-binding cassette transporter A1 (ABCA1) gene which encodes for the ABCA1 membrane transporter. The ABCA1 gene is located on chromosome 9q22-q31 and it contains 50 exons that spans 150 kb. Allele heterogeneity is highly prevalent in TD. Currently over 200 disease associated mutations have been identified in TD afflicted patients. Two-thirds of the mutations associated with TD are missense mutations while the remaining are nonsense or frameshift mutations. Though disease causing mutations have been documented throughout the ABCA1 gene, the most common mutations occur in the exons encoding the extracellular domain and the ATP-binding cassettes which are the nucleotide binding domains of the ABCA1 membrane transporter.

The ABCA1 gene encodes for the ABCA1 membrane transporter. Similar to other ATP-binding proteins, the ABCA1 membrane transporter is composed of two ATP-binding domains and two trans-membrane domains. Normally, ABCA1 is activated by protein kinases and is modified at the transcriptional level by increased cellular cholesterol stores. The ABCA1 transporter is important in the reverse cholesterol transport pathway. In normal individuals the ABCA1 is important in the release of free cholesterol and phospholipids from peripheral cells which are then transferred to lipid-poor apolipoprotein A-I (Apo A-I) and HDL particles. Mutations in the ABCA1 gene result in deficits in fully functional ABCA1 transport protein resulting in high levels of cholesterol esters in tissues and low levels of HDL cholesterol and Apo A-I particles. Though TD is an autosomal recessive disorder which means affected individuals must be homozygous for the same gene to show the phenotype, heterozygotes show an intermediate phenotype for TD. Heterozygotes which are carriers for the disease allele and do not exhibit the phenotype for TD have shown low HDL cholesterol and approximately 50% decrease in ABCA1-mediated cell cholesterol release. This has been interpreted as an intermediate phenotype observed in heterozygotes .Mxc47 (talk) 08:36, 1 December 2016 (UTC)

Diagnosis
Tangier disease (TD) can be detected through genetic screenings for a mutation on the ABCA1 protein in chromosome 9q31. However, this mutation can be difficult to detect so most diagnosis are based on clinical features the patient shows. Rhrth9 (talk) 06:49, 1 December 2016 (UTC)

The ABCA1 protein consists of two six trans-membrane domains that are connected to each other by a highly hydrophobic region. Mutations occur usually near the first trans-membrane domain of the protein and can cause inactivation of the protein as a whole. Inactivation of ABCA1 protein can lead to several symptoms listed above. Rhrth9 (talk) 06:49, 1 December 2016 (UTC)