Scientific background:

Summary: Mutations that result in defective apolipoprotein B cause a rare but severe disease, abetalipoproteinemia. More common are mutations with impared LDL receptor binding and elavated LDL cholesterol.

Gene: Apolipoprotein B (ApoB) exists in two different versions called ApoB100 and ApoB48. In enterocytes a posttranscriptional modification of the mRNA takes place. As a result of this modification a stop codon is generated and translation is aborted when 48% of the protein is synthesized. There is no LDL rececptor ligant in ApoB48.

Pathology: ApoB100 is secreted by hepatocytes togesther with VLDL. Enterocytes secrete ApoB48 in chylomikrones. Functioning ApoB100 can be reabsorbed by hepatocytes via LDL rececptor. Chylomikrons containing ApoB48 hepatocytes by other mechanisms. Mutations in ApoB100 affecting the ligand lead to increase of cholesterol rich LDL particels. The effect is just the same as in LDL rececptor mutations.

Clinical signs: Phenotypicaly there is no difference beween mutations affecting ligand region in ApoB100 and LDL rececptor mutations. Patients have a significant hypercholesterinemia. In lipidelektrophoresis we see a predomination of LDL particles According to Fredrickson this hyperlipemia is classifyed typ II. The chance for oxydation of these particles and by this way the risk for cardiovascular disease is hight.

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

Interpretation: Apolipoprotein B mutations and LDL rececptor mutation should be screened together.

Methodology:

	clinical test	Method		Genomic sequencing of the entire coding region
		Turn-around time		25 working days
		Effort		large
		Specimen		DNA
		Quality assessment		Internal quality control only
	All known and new missense, nonsense and splice mutations can be detected.
	clinical test	Method		Hotspot sequencing
		Turn-around time		25 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	Only in the region of interest, known and new missense, nonsense and splice mutations can be detected.
	clinical test	Method		Carrier testing
		Turn-around time		25 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: 

Soria LF et al. (1989) Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100.
Vrablík M et al. (2001) Major apolipoprotein B-100 mutations in lipoprotein metabolism and atherosclerosis.
Schonfeld G et al. (2005) Familial hypobetalipoproteinemia: genetics and metabolism.
Whitfield AJ et al. (2004) Lipid disorders and mutations in the APOB gene.
Schonfeld G et al. (2003) Familial hypobetalipoproteinemia: a review.
Parhofer KG et al. (2006) Thematic review series: patient-oriented research. What we have learned about VLDL and LDL metabolism from human kinetics studies.