Week 7: Familial hypercholesterolaemia + Coronary Heart Disease

Question 1

CHD stats

Answer 1

• 9.1 million per year in the world die from CHD
• 66000 per year in the UK
• Atherosclerosis of coronary artery is generally the underlying cause of CHD

Question 2

Lipoproteins structures

Answer 2

• Structure has a surface monolayer of phospholipids, non-esterified cholesterol + protein
• Have core cholesteryl ester + triacylglycerol + some non-esterified cholesterol

Question 3

Lipoprotein types

Answer 3

• Chylomicrons
• Very low density lipoprorteins (VLDL)
• Low density lipoprotein (LDL)
• High density lipoprotein (HDL)

Question 4

LDL

Answer 4

• 25nm in diameter
• OCmposed of 75% lipids,mainly cholesteryl ester + 25% protein (apolipoprotein B-100)

Question 5

LDL receptor gene

Answer 5

• Located on short arm of ch19 in humans
• 45kb
• 18 exons + 17 introns
• Possible assembled by exon shuttling

Question 6

LDL receptor gene structure

Answer 6

• Exon 1 codes for 21 aa signal sequence
• Exon 2-6 codes for ligand-binding domain, containing 7 repeats of 40 aa each, similar to complement proteins, each repeat is heald together by Ca2+
• Exon 7-14 codes for domain homologus to epidermal growth factor precursor, required for dissociation of LDL at acidic pH
• Exon 15 codes for domain with O-linked oligosaccharides attached
• Exon 16 + part of 17 codes for membrane spanning domain
• Remainder of exon 17 + part of 18 codes for cytosolic domain
• Remainder of exon 18 is untranslated

Question 7

Familial hypercholersterolaemia (FH)

Answer 7

• Most common monogenic genetic disease, almost always autosomal
• Heterozygous: 1/500 or 1/200 in more recent disease
• Homozygous: 1/~250,000
• Caused by mutations in LDL receptor
• 1700 different mutations discovered so far

Question 8

Diagnosing LDL receptor mutations

Answer 8

• Not all cases require genome reading/screening
• If severe, then next gen sequencing LdL, apoB-100, ARH-1 + PGSK9
• If necessary, screening of closely related family (Cascade screening)
• Can include:
  + Class 1 mutations
  + Class 2 mutations
  + Class 3 mutations
  + Class 4 mutations
  + Class 5 mutations

Question 9

Class 1 mutations

Answer 9

• Little or no LDL receptor protein produced
• Primarily causes mutations in LDL receptor promoter
• Some produced no LDL receptor mRNA
• Most mutations produce normal functional mRNA but deficient
• Some produce truncated mRNA

Question 10

Class 2 mutations

Answer 10

• Defective transfer from endoplasmic reticulum to golig complex
• Due to mutations in ligand-binding domain or EFG precursor homology domain
• LDL receptor stays in ER + is eventually degraded

Question 11

Class 3 mutations

Answer 11

• Defective binding LDL
• Substitutions/rearrangements of cysteine-rich repeats of ligand-binding domain/EGF precursor homology domain may be affected