Scientific background:

Summary: The lipoprotein receptor encoded by this gene allows liver cells to eliminate LDL particles from the blood. Mutations result in impaired function, which becomes noticable by elevated LDL cholesterol levels, cholesterol accumulation in the body, and accelerated arteriosclerosis.

Gene: The gene of the low density lipoprotein receptor (LDLR) is about 45kb in size. I consists of 19 exons. Locus is on chromosome 19 (19p13.2). Structure and function of the protein domains are well known and explained here: www.nephrogene.de.

Pathology: The task of this receptor is reabsorption of LDL particles from the blood stream into the hepatocytes. Apolipoprotein B is the corresponding ligand on LDL. If this reabsorption is disturbed the cholesterol rich LDL particles remain in the blood stream for a long time and they get oxidated and reabsorbed by scavanger receptors in some other cells including the endothelial cell. This initiates the process leading to artherosclerosis.

Clinical signs: Biochemically we find a hyperlipimia of type IIa according to Fredrickson. But often a mutation of this gene is accompanied by other metabolic disturbancies and therefore Triglycerides may be elavated too. The typical clinical picture are xanthomas. You can find some examples following this link: www.nephrogene.de/.

Epidemiology: The prevalance of the homozygous form is 1:1.000.000. The allel frequency is 1:500.

Interpretation: Mutations in have a great importance for the development of coronary heart disease.

Test strategy: Patients with hypercholesterolemia, when lipidapheresis is considered in therapy.

Methodology:

	clinical test	Method		Genomic sequencing of the entire coding region
		Turn-around time		25 working days
		Effort		medium
		Specimen		DNA
		Quality assessment		Internal quality control only
	All known and new missense, nonsense and splice mutations can be detected.
	clinical test	Method		Multiplex Ligation-Dependent Probe Amplification
		Turn-around time		25 working days
		Effort		medium
		Specimen		DNA
		Quality assessment		Internal quality control only
	clinical test	Method		Carrier testing
		Turn-around time		5 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	The test is only specific about the mutation already known in this kindred.

Literature: 

Tybjaerg-Hansen A et al. (1998) Association of mutations in the apolipoprotein B gene with hypercholesterolemia and the risk of ischemic heart disease.
Schuster H et al. (1998) DNA diagnosis of familial hypercholesterolemia.
Varret M et al. (1997) Software and database for the analysis of mutations in the human LDL receptor gene.