LDL receptor mutations

FFI is transmitted as an autosomal dominant trait, so even heterozygotes (frequency of 1 in 500) for LDL receptor mutations have an increased risk of atherosclerosis. 

LDL receptor mutations can be divided into five different functional classes as shown in Figure 14-1. Class 1 mutations (null alleles) do not produce immunoprecipitable protein. Class 2 mutations produce proteins that are not (completely, 2A partially, 2B) transported to the Golgi due primarily to defective folding of the protein, which is then targeted for degradation. Class 3 mutations produce proteins that are normally transported to the plasma membrane but do not bind to LDL normally. Class 4 mutations... 

Four classes of LDL receptor mutations have been identified. Class 1 mutations are characterized by the failure of expression of the receptor protein. It is possible, however, that a modified protein is produced but it is not recognized as an LDL receptor protein. Class 2 mutations involve a nonsense mutation (premature termination of protein synthesis Chap. 17), and result in a defect in the transfer of the receptor from the endoplasmic reticulum to the cell membranes. This class of mutation is common in Afrikaners and Lebanese. The Watanabe heritable hyperlipidemic rabbit (WHHL) is an animal model which has a Class 2 defect and has been used extensively for the study of familial hypercholesterolemia. Class 3 mutations result in abnormal binding of LDL. This can be caused by alterations in the amino acid sequence of Domain 1. Class 4 mutations are those with defective internalization due to the receptor s inability to be located in coated pits. This is the result of mutations in the fifth, C-terminal domain. 

The molecular defect in most cases of familial hypercholesterolemia is an absence or deficiency of functional receptors for LDL. Receptor mutations that disrupt each of the stages in the endocytotic pathway have been identified. Homozygotes have almost no functional receptors for LDL, whereas heterozygotes have about half the normal number. Consequently, the entry of LDL into liver and other cells is impaired, leading to an increased plasma level of LDL. Furthermore, less IDL enters liver cells because IDL entry, too, is mediated by the LDL receptor. Consequently, IDL stays in the blood longer in familial hypercholesterolemia, and more of it is converted into LDL than in normal people. All deleterious consequences of an absence or deficiency of the LDL receptor can be attributed to the ensuing elevated level of LDL cholesterol in the blood. 

Familial hypercholesterolemia. Several classes of LDL-receptor mutations have been identified as causes of this disease. Suppose that you have been given cells from patients with different mutations, an antibody specific for the LDL receptor that can be seen with an electron microscope, and access to an electron microscope. What differences in antibody distribution might you expect to find in the cells from different patients ... 

Classification of the defects of naturally occurring mutant human V2 receptors can be based on a scheme similar to that used for the LDL receptor. Mutations have been grouped according to the function and subcellular localization of the mutant protein whose cDNA has been transiently transfected in a heterologous expression system [133]. Using this classification, type 1 mutant V2 receptors reach the cell surface but display impaired ligand binding... 

Molecular genetic studies in FH patients have identified close to 700 different mutations in the LDL receptor gene. Comprehensive information about LDL receptor mutations in FH patients can be found at http //www.ucl.ac.uk/fh/, and a useful reference for LDL receptor mutations in Europe is Ref. [7]. In order to gain insight into the nature of these mutations, they are grouped into five classes according to their effects on the protein as follows. 

Defects in the LDL receptor have been particularly well explored as a basis of the disease familial hypercholesterolemia (93,111). A number of defects that collectively impair LDL receptor trafficking, binding, or deUvery underHe this disease where LDL and semm cholesterol rise to levels that mediate early cardiovascular mortaUty. Studies of the population distribution of this defect can determine the source of the original mutation. Thus, in Quebec, about 60% of the individuals suffering from familial hypercholesterolemia have a particular 10-kdobase deletion mutation in the LDL gene (112). This may have arisen from an original founder of the French Canadian settiement in the seventeenth century. 

LRP4 is another receptor of the LDL receptor gene family involved in regulation of embryonic patterning, mainly controlling formation of limb structures. Loss of receptor activity in gene targeted mice or spontaneous mutation in bovine cause abnormal limb development and... 

Famiiiai hyperchoiesteroiemia (type iia) Defective LDL receptors or mutation in ligand region of apo B-100. Elevated LDL levels and hypercholesterolemia, resulting in atherosclerosis and coronary disease. 

Familial hypercholesterolemia (MIM 143890) Mutations in the gene encoding the LDL receptor... 

Familial hypercholesterolaemia is characterized by a significant elevation in plasma LDL concentration. The basic metabolic defect appears to be abnormal LDL receptor function, arising from mutations in the LDL receptor gene. Several receptor mutations have been identified and hypercholesterolaemia severity as well as the age of onset of ischaemic heart disease has recently been demonstrated to vary according to the type of LDL receptor gene defect (Moorjani et al., 1993). 

Moorjani, S., Betard, C., Brun, D., Roy, M., Gagne, C., Davignon, J., Torres, A., Lambert, M. and Lupien, P. (1993). Mutations of the LDL receptor gene, variations in plasma cholesterol and expression of coronary heart disease in homozygous familial hypercholesterolaemia. Lancet 341, 1303-1306. 

LDL-receptor negative Reduction in LDL receptors Single nucleotide mutation Metabolic and environmental Overproduction of VLDL and/or LDL... 

Familial hypercholesterolemia (FH) is an autosomal dominantly inherited disease caused by mutations in the gene for the LDL receptor. Up to now more than 680 distinct mutations, distributed over the entire gene, have been described [42]. Heterozygous FH individuals express only half the number of functional LDL-r and, therefore, have a markedly raised plasma cholesterol and usually present with premature coronary artery disease. Homozygous FH individuals are more severely affected and may succumb before the age of maturity. The prevalence of heterozygous FH is approximately 1 in 500 in Caucasians. 

Karayan L, Qiu S, Betard C, Dufour R, Roederer G, Minnich A, et al. Response to HMG CoA reductase inhibitors in heterozygous familial hypercholesterolemia due to the 10-kb deletion ( French Canadian mutation ) of the LDL receptor gene. Arteriosder Thromb 1994 14 1258-1263. 

Soutar, A. K., McCarthy, S. N., Seed, M., and Knight, B. L., Relationship between apopro-tein(a) phenotype, lipoprotein(a) concentration in plasma and low-density lipoprotein (LDL) receptor function in a large kindred with Familial Hypercholesterolemia due to the Pro Leu mutation in the LDL-receptor gene. J. Clin. Invest. 88, 483-492 (1991). 

Scientists studying a common mutation in the LDL receptor gene have inserted the defective gene into fertilized murine ova. The altered ova are implanted in a firster mother and the progeny are used to study the effects of the mutant allele. The mice produced in this procedure would be referred to as ... 

I Coronary heart disease can be caused by mutations in the LDL receptor (familial hypercholesterolemia), inherited cancer syndromes can result from mutations in ... 

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. 

Familial hypercholesterolemia (FH) results from inherited deficiency or mutation of the LDL receptor and consequent impairment of uptake and processing of LDL-cholesterol by the liver. 

The many different LDL receptor gene mutations that lead to FFI can be classified into five groups according to the functional defect in the receptor ... 

The answer is D. This patient s tests indicate that he has severe hypercholesterolemia and high blood pressure in conjunction with atherosclerosis. The deaths of several of his family members due to heart disease before age 60 suggest a genetic component, ie, familial hypercholesterolemia. This disease results from mutations that reduce production or interfere with functions of the LDL receptor, which is responsible for uptake of LDL-cholesterol by liver cells. The LDL receptor binds and internalizes LDL-choles-terol, delivers it to early endosomes and then recycles back to the plasma membrane to pick up more ligand. Reduced synthesis of apoproteins needed for LDL assembly would tend to decrease LDL levels in the bloodstream, as would impairment of HMG CoA reductase levels, the rate-limiting step of cholesterol biosynthesis. Reduced uptake of bile salts will also decrease cholesterol levels in the blood. 

The genetic change that produced the mutant LDL receptor in these cases can be classified as which type of mutation ... 

Hobbs HH, Russell DW, Brown MS, Goldstein JL. The LDL receptor locus in familial hypercholesterolemia mutational analysis of a membrane protein. Annu Rev Genet 1990 24 133-170. 

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