A 32 year old African American woman, who was healthy, fertile and normotensive, with normal liver and renal function, was found to have a very low serum LDL cholesterol level, of only 14 mg/dl. What mutation might be causing such low LDL cholesterol levels in this individual, given that there are no changes in the APOB gene? Explain the risk of coronary heart disease in this individual, the function of the affected protein, and any additional features which you might expect this individual to display. | Academic Papers Help
- A 32 year old African American woman, who was healthy, fertile and normotensive, with normal liver and renal function, was found to have a very low serum LDL cholesterol level, of only 14 mg/dl. What mutation might be causing such low LDL cholesterol levels in this individual, given that there are no changes in the APOB gene? Explain the risk of coronary heart disease in this individual, the function of the affected protein, and any additional features which you might expect this individual to display.
- PCSK9: proprotein convertase subtilisin/kexin type 9
- PCSK9: linked to familial autosomal dominant hypercholesterolaemia (ADH) (i.e. very high levels of LDL cholesterol, which is inherited in an autosomal dominant (one defective allele: phenotype) manner in families). In the last decade, families with ADH identified which were NOT due to mutations in LDL receptor or apoB, but which had very high LDL cholesterol (>200mg/dl)
- The gene responsible was mapped to chromosome 1p32 in differing populations: missense mutations result in gain of function of PCSK9, resulting in a severe hypercholesterolaemia
- Also identified as a gene repressed by high cholesterol levels in mice, using microarray/genomic scans; the statin drugs increase the expression of the protein important as this implies that PCSK9 may limit the ability of statin drugs to increase expression of the LDL receptor and lower plasma cholesterol levels.
- PCSK9 is a chaperone protein, which regulates the degradation of the LDL receptor. It is a member of a subtilisin family (proteases), and is produced as a 72kDa inactive (zymogen) protein in the endoplasmic reticulum. It self-cleaves in the Golgi to give a 60-63kDa active protein, which can be secreted into the bloodstream
- PCSK9 is produced in the liver, kidney, brain, skin and small intestine during embryo development, but in adults is thought to be restricted mainly to the liver and kidney.
- PCSK9 autocatalysis triggers its secretion, so that it can interact with the LDL receptor, either within the pathway, or at the cell surface. However, the protein does not degrade the LDL receptor. Instead, it binds (1:1 ratio) to the EGF precursor homology domain of the LDL receptor, targeting the LDL receptor for degradation instead of recycling back to the plasma membrane. This means that fewer LDL receptors are available in the liver to take up LDL from the bloodstream, and serum cholesterol levels rise.
- If PCSK9 is overexpressed in mice severe hypercholesterolaemia results, but only in mice expressing the LDL receptor. If the LDL receptor is absent, then PCSK9 overexpression has no effect. Equally, if PSCK9 is genetically deleted, then hepatic levels of the LDL receptor increase around 3-fold, reducing blood concentrations of LDL cholesterol about 5-fold.
- The severity of the hypercholesterolaemia associated with PCSK9 mutations varies depends upon the residues affected but the most severe form detected to date is the D374Y amino acid substitution, which increases the activity of PCSK9. British patients who are heterozygous for D374Y mutation suffer from coronary artery disease around 10years earlier than individuals without this mutation.
- The D374Y variant causes gain of PCSK9 function, increasing affinity for the LDL receptor by 28-fold, so that more is degraded; also associated with greater secretion of PCSK9 oligomers (multiple proteins) so that more LDL receptors are degraded.
- Loss of function mutations in PCSK9 lower plasma LDL cholesterol, and protect against coronary heart disease arguing that PCSK9 is a good target for therapeutic drugs, antibodies or SiRNA knockdown. Some of these ideas have been tested and proven to work in murine models.
- Downsides to loss of PCSK9: Glucose intolerance, elevated BP (?), inflammatory responses, apoptosis (493 words!)
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A 32 year old African American woman, who was healthy, fertile and normotensive, with normal liver and renal function, was found to have a very low serum LDL cholesterol level, of only 14 mg/dl. What mutation might be causing such low LDL cholesterol levels in this individual, given that there are no changes in the APOB gene? Explain the risk of coronary heart disease in this individual, the function of the affected protein, and any additional features which you might expect this individual to display. | Academic Papers Help
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