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Familial hypercholesterolemia: genetic diagnosis

that coronary lesions measured by coronary angiography in SCOR,28 LARS,29 L-CAPS,30 LAARS and FHRS,31,32 or by intracoronary ultrasonography in LACMART;33 aortic lesions evaluated by transesophageal echocardiography;34 carotid intima-media thickness measured by quantitative B-mode ultrasound in ASAP;35 endothelial dysfunction measured by flow mediated dilatation and E-selectin;36 myocardial ischemia detected by exercise test in LAARS;31 and myocardial perfusion abnormalities assessed by digi- tal angiography in LAARS,37 all improve with aggressive LDLc reduction obtained with LDL apheresis and/or lipid lowering drugs.

Consistent with these findings, the use of lipid lowering drugs, especially methylglutaryl coenzyme A (HMGCoA) reductase inhibitors, has been shown to be associated with improved cardiovascular prognosis without any change in noncardiovascular mortality in FH subjects on the Simon Broome Register in the United Kingdom.18

The LDL receptor

The LDLr is synthesized as a 120 KDa precursor protein. The glycosylated mature receptor reaches the cell surface and is directed towards clathrin-coated pits where it binds to Apo B-enriched and apolipoprotein E (Apo E)-enriched lipoproteins via its extracellular domain (Figure 1).38 The complex is endocytosed and migrates to the endosomes. Upon acidification of the endosomal pH, the LDL particle is released and later degraded in lysosomes. The LDLr returns to the membrane and enters in a new cycle. There is extensive evidence that plasma PCSK9 raises LDLc levels by binding to cell surface LDLr and targeting the receptor to lysosomes for degradation.39,40

The LDLR is mapped to 19p13.1–13.3, spans 45,000 base pairs (bp), and codifies for an ubiquitous transmembrane glycoprotein of 839 amino acids that mediates the transport of LDL into cells via endocytosis.41 It contains 18 exons and 17 introns encoding the six functional domains of the mature

LDL

APOB

Clathrin-coated pits

LDLr

ARH

Endosome

PCSK9 Idol

Synthesis

Recycling

ER GOLGI

Lysosome

Figure 1 The LDL receptor pathway. Notes: The low-density lipoprotein receptor (LDLr) is synthesized as a 120 KDa precursor protein and processed in the golgi apparatus (GOLGi) producing the glycosylated mature receptor that is transported to the cell surface and is directed towards clathrin-coated pits through interactions involving LDL particle, enriched with apolipoprotein B (APOB) where it binds to LDL particle. The complex is transported to endosomes where the acidic pH causes a dissociation of the receptor–ligand complex, releasing the LDLr to its recycling so the LDL is degraded in the lysosomal compartment. The proprotein convertase subtilisin/kexin type 9 (PCSK9) and idol protein participate in a decreasing of receptor recycling and increasing the LDLr degradation.

The Application of Clinical Genetics 2010:3

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