Presentation on theme: "Familial Hypercholesterolemia By: Kasarah Allen City College of New York Frederick Douglass Academy."— Presentation transcript:
Familial Hypercholesterolemia By: Kasarah Allen City College of New York Frederick Douglass Academy
Abstract Patients suffering from familial hypercholesterolemia have a much more serious condition than those people who have high levels of cholesterol. These FH patients have a much higher chance of suffering from heart attacks and stroke. Hypercholesterolemia describes the people with high levels of cholesterol. In other words, the people who have too much cholesterol circulating in their bloodstream. It is known to be caused by the consumption of a high-cholesterol diet and/or the genetic disease familial hypercholesterolemia (FH). Human body usually produces about two- thirds of its needed cholesterol in the liver, thus very little supplement of cholesterol is required. The homozygous FH is more rare, occuring with the frequency of about 1 in a million. The statistics for the homozygous FH is not surprising though, since patients suffering from two alleles of this gene usually do not survive pass their teens. The condition of hypercholesterolemia in FH patients are detectable at birth or shortly thereafter. The cholesterol levels in heterozygous patients are between350 to 500 mg/dL, and in homozygous, the levels are between 700 to 1,200 mg/dL. Hypercholesterolemia is a silent disease. No symptoms will occur until the resulting chest pain of a heart attack or the symptoms of a stoke. Tendon xanthomas commonly occur in FH patients. The heterozygous will develop these later in life, but the homozygous usually develops them in their childhood. Xanthomas are lesions caused by cholesterol deposits in various parts of the body. The common places are in the extensor tendons of the hands and eyelids (know as xanthelasmas).
Introduction Familial hypercholesterolemia (FH) is a genetic disease in which patients have greatly elevated levels of serum cholesterol and suffer from heart attacks early in life. Although moderate hypercholesterolemia is a common finding in industrialized countries, heterozygous FH occurs in approximately 1 per 500 persons worldwide. FH is a disorder of absent or grossly malfunctioning low-density lipoprotein (LDL) receptors.
Background In 1972, Michael S. Brown and Joseph L. Goldstein hypothesized that surmised that cholesterol overproduction results from defect in the control mechanisms that normally regulate cholesterol biosynthesis. In 1974, Brown and Goldstein demonstrated that the lesion in FH cells is a defect in LDL binding to a receptor on the surface.
LDLR PDB code: 1N7D The low-density lipoprotein receptor mediates cholesterol homeostasis through endocytosis of lipoproteins. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. The LDL receptor gene is located on the short arm of chromosome 19, and the protein is composed of 860 amino acids.
The importance of the LDL Receptor The addition of LDL to the normal human fibroblasts inhibits the activity of 3-hydroxy-3 methylglutaryl coenzyme A reductase (HMG-Co A reductase), the rate-limiting enzyme in the cholesterol biosynthetic pathway. HMG-Co A reductase activity is unaffected by addition to LDL to the cells of FH patients, resulting in over production of cholesterol by FH cells.
The importance of the LDL Receptor cont’d Goldstein and Brown discovered the LDL receptor and determined that FH was caused by an autosomal dominant mutation. Since then, more than 700 mutations have been identified that have a meaningful impact on receptor function. LDL receptor function ranges from completely absent to approximately 25% of normal receptor activity.
Comparison Comparison between humans and pacific oysters using FASTA >gi| |pdb|1N7D|A Chain A, Extra cellular Domain Of The Ldl Receptor Length=699 Score = 51.6 bits (122), Expect = 6e-05, Method: Composition-based stats. Identities = 32/70 (45%), Positives = 32/70 (45%), Gaps = 0/70 (0%) Query 287 DIQAPXGLAVXXIXSNIYXXXXVLXXXXXXXXXX XXXXXXXXXXXXXXXXIVVXPVHGFM 346 DIQAP GLAV I SNIY VL IVV PVHGFM Sbjct 451 DIQAPDGLAVDWIHSNIYWTDSVLGTVSVADTKG VKRKTLFREQGSKPRAIVVDPVHGFM 510 Query 347 YXTXXGTPAK 356 Y T GTPAK Sbjct 511 YWTDWGTPAK 520gi| |pdb|1N7D|A
Protein Modeling MOE is used for homology or comparative modeling of protein three-dimensional structures. The user provides an alignment of a sequence to be modeled with known related structures and MOE automatically calculates a model containing all non-hydrogen atoms. MOE implements comparative protein structure modeling by satisfaction of spatial restraints, and can perform many additional tasks
Structure Prediction This structure was created by Moe. It’s the template for the LDLR protein. This is what the LDLR protein would look like based on similar protein of the same gene.
Space Filling Model Space filling molecular models show the relative atomic sizes of the atoms of the molecule. This model shows the carbons (gray), hydrogen's (light gray), oxygen (blue), carbon monoxide's (red), and sulfur (yellow) of the protein.
Further Studies Curing homozygous patients is very difficult because they express little or no activity from the LDL receptor. They are resistant to most cholesterol-lowering drugs. Liver transplantation can provide the missing LDL receptors but requires special long-term follow-up cares for the transplanted organs, including continuous immunosuppressants. FH homozygous are currently treated with modified forms of plasmapheresis that selectively remove very small density lipoprotein and low-density lipoproteins from the plasma. Also, the modern approach to this problem is gene therapy.
Further Studies Continued Knowing the structure of the LDL receptor scientists can better understand the effects it has on Familial Hypercholesterolemia patients. For example, scientist can find why the LDL receptor fails to activate and bind to the surface and can learn how to provide LDL receptors to FH patients.