Human LDL receptor gene

The human LDL receptor gene organization and naturally occurring mutations. 562... 

The 48-kb human LDL receptor gene contains 18 exons and is localized on the distal short arm of chromosome 19. There is a strong correlation between the functional domains... 

Transgenic animal models with spontaneous or induced receptor gene defects have been instrumental in elucidating the physiological roles of the LDL receptor gene family. In addition, a number of human diseases have been identified that are caused by sporadic or inherited forms of receptor deficiency (Table 1). 

Low-density Lipoprotein Receptor Gene Family. Table 1 Human diseases of the LDL receptor gene family... 

With a population frequency of 1 in 500, heterozygous FH is one of the most common human genetic anomalies. In contrast, homozygotes (individuals who have inherited a defective LDL receptor gene from both parents) are rare (approximately one in one million). These patients have plasma cholesterol values of 650-1200 mg/100 mL. Both xanthomas and heart attacks occur during childhood or early adolescence. Death usually occurs before the age of 20. 

In summary, to a large extent through the delineation of natural mutations in the LDL receptor gene, structural as well as regulatory features of receptor-mediated metabolism of the major cholesterol-carrying lipoprotein in human plasma are now thought to be well understood. Nevertheless, very recent smdies have revealed that there are additional mechanisms for control of LDL receptor activity two of these modulatory mechanisms and their key components are outlined in the next section. 

Alu sequences in DNA were named for the enzyme Alu (obtained from Arthrobacter luteus), that which is able to cleave them. Alu sequences make up 6 to 8% of the human genome. In some cases of familial hypercholesterolemia, homologous recombination is believed to have occurred between two Alu repeats, resulting in a large deletion in the low- density lipoprotein (LDL) receptor gene. The LDL receptor mediates uptake of the cholesterol-containing LDL particle into many cell types and, in the absence of functional LDL receptors, blood cholesterol levels are elevated. Patients who are homozygous for this mutation may die from of cardiac disease as early as in their second or third decade of life. 

Plump, A.S., Masucci-Magoulas, L., Bruce, C., Bisgaier, C.L., Breslow, J.L., and Tall, A.R. (1999) Increased Atherosclerosis in ApoE and LDL Receptor Gene Knock-Out Mice as a Result of Human Cholesteryl Ester Transfer Protein Transgene Expression, Arten ojder. Thromb. Vase. Biol. 19,1105-1110. 

R. R., and Johnson, M.L. (2002) A Mutation in the LDL Receptor Related Protein 5 Gene Results in the Autosomal Dominant High Bone Mass Trait. American Journal of Human Genetics 70, 11-19. 

VanWesenbeeck, L., Cleiren, E., Gram, J., Beals, R.K., Benichou, 0., Scopelliti, D., Key, L., Renton, T., Bartels, C., Gong, Y., Warman, M.L., DeVernejonl, M-C., Bollerslev, J., and VanHnl, W. (2003) Six Novel Missense Mutations in the LDL Receptor-Related Protein 5 (LRP5) Gene in Different Conditions with an Increased Bone Density. American Journal of Human Genetlcsll, 763-771. 

Apo E is a protein found in VLDLs, LDLs, and HDLs (Table 18.1). With a molecular weight of 33,000, Apo E is involved in binding lipoprotein complexes to the LDL receptor. Apo E is found in the human Apo C-II gene cluster and a variant of Apo E has been associated with an increased risk for Alzheimer s disease. 

The second area of growing importance is that of susceptibility to disease. It has long been known that some common diseases run in families, although it was not known why. For the same reason, known disease risk factors carry very different levels of risk for different individuals. For example, in Topic 19 we met LDL, one of the proteins associated with transport of cholesterol. This has to dock with a specific protein receptor, the LDL receptor, at cell surfaces. A variety of mutations in the gene for the LDL receptor cause familial hypercholesterolaemia affected individuals have a much enhanced risk of heart disease. Detailed study of the human genome is likely to throw up many more correlations of this kind for various kinds of cancer and other diseases. It has recently been found that a polymorphism related to survival of mediaeval plague epidemics may also be responsible for certain individuals remarkable resistance to the HIV infection that causes AIDS ... 

In monkeys fed diets containing cholesterol and various fats, CETP activity was found to be positively correlated only with LDL particle diameter and negatively correlated with LDL receptor function in the SFA group (32). Polymorphisms in CETP and lipoprotein lipase genes also appeared to be involved in the cholesterolemic response of dietary fats in humans (33). 

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