Tangier Disease and ABCA1
This web page was produced as an assignment for Genetics 677, an undergraduate course at UW‐Madison.

Picture
HDL particle [9]


Tangier Disease, 
ABCA1 and 

Cholesterol Transport

About Tangier disease

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Swollen tonsils of a patient with Tangier disease [2]
Tangier disease is a disorder of cholesterol metabolism caused by mutations in the gene ATP-binding cassette A1 (ABCA1) [1][8].

The disorder is sometimes also referred to as familial high density lipoprotein deficiency, familial alphalipoprotein deficiency, and analphalipoproteinaemia [1] .

Symptoms, which occur as a result of accumulation of cholesterol esters in certain tissues, include:
  • Swelling and yellowish discoloration in the tonsils, spleen, skin and liver [1]
  • Clouded corneas [1]

This accumulation occurs when blood levels of high density lipoprotein (HDL), also known as "good cholesterol", become very low. HDL normally functions to remove "bad cholesterol" (low density lipoprotein - LDL) from the blood. Without HDL, LDL deposits form and create a suite of health problems for the patient [1][2].


Disease prevalence

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"Heat map" of Tangier disease incidence in the United States between 11865 and 2009 [10]
Tangier disease is very rare, with approximately one hundred known cases worldwide [2]. The NIH officially classifies it as a "rare disease", meaning that it affects less than 1/200,000 people [3].

The disease was named for Tangier Island off the coast of Virginia in the United States, where it was first characterized in two siblings in 1961 [4].


The ABCA1 protein and HDL efflux

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Predicted structure of ABC1 in the plasma membrane [6]
ABC1 is a member of the ATP binding cassette protein superfamily - a group of proteins that use energy from hydrolysis of adenosine triphosphate (ATP) to transport molecules out of cells and into the bloodstream [5][6]. 

ABC1 localizes to cell plasma membranes, where it transports cholesterol and lipids into the cell. The protein is present in all cells, but is most prevalent in the liver, small intestines and macrophages (white blood cells) [6].

Normally, these substances are used to form high‐density 
lipoprotein - HDL - upon their release from cells [5].

How do mutations in ABCA1 cause Tangier disease?

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The role of ABCA1 in cholesterol transport and HDL formation [7]

  1. In Tangier disease cases, mutated ABC1 cannot transport cholesterol out of the liver, macrophages and intestinal epithelial cells into nascent HDL particles
  2. With only this cholesterol-poor HDL, excess cholesterol cannot be effectively removed from the body
  3. Cholesterol accumulates in cells and the bloodstream, resulting in the characteristic symptoms of Tangier disease 
  4. Without HDL to remove cholesterol from the bloodstream, LDL particles accumulate and form plaques, causing atherosclerosis 

                                                            [7]



Related disease: atherosclerosis

Atherosclerosis: cholesterol (LDL) deposits forming in an artery [7]
When blood LDL levels remain chronically high, the LDL particles can form cholesterol deposits in the blood vessel walls that cause scarring (atherosclerosis) [7].

Atherosclerotic plaques inhibit blood flow, weaken vessels and increase the risk of blockage by blood clots (thrombi), which can cause heart attacks and strokes when a plaque ruptures.

Much of the research interest in ABCA1 is rooted in its connections to atherosclerosis, which is a leading cause of death in the United States and worldwide.



Sources:

1. http://ghr.nlm.nih.gov/condition/tangier‐diseasehttp://profiles.nlm.nih.gov/AA/A/A/D/L/_/aaaadl.html

2. http://profiles.nlm.nih.gov/AA/A/A/D/L/_/aaaadl.html

3. http://rarediseases.info.nih.gov/GARD/Condition/7731/Tangier_disease.aspx

4. Fredrickson, D.S., Altrocchi, P.H., Avioli, L.V., Goodman, D.S. & Goodman, H.C. Tangier disease: Combined clinical staff conference at the National Institute of Health. Ann. Intern. Med. 55, 1016−1031 (1961).

5. http://www.genecards.org/cgi-bin/carddisp.pl?gene=ABCA1&search=ABC1

6. Maxfield F and Tabas I. Role of cholesterol and lipid organization in disease. Nature. 2005; 438: 612-621.

7. Rader D and Daugherty A. Translating molecular discoveries into new therapies for atherosclerosis. Nature 451, 904-913 (21 February 2008) | doi:10.1038/nature06796l

8. Rust S. et al. Tangier disease is caused by mutations in the gene encoding ATP‐binding cassette transporter 1. Nat Genet. 1999 Aug; 22(4):316–8. 

9. http://www.clinicalcorrelations.org/?p=44
10. http://biogps.gnf.org/#goto=genereport&id=19Tis

Created by Andrea Slavney - Senior at UW-Madison (Genetics & Anthropology)
[email protected]
Last updated: 5/16/2011