Family hypobetalipoproteinemia (Familial hypobetalipoproteinemia -FHBL-) - Genes and ANGPTL3 APOB

Family hypobetalipoproteinemia (FHBL) is an altered lipid which results in low levels of blood cholesterol. The severity of signs and symptoms that people with FHBL vary widely. More mildly affected people have some problems with the absorption of dietary fats and no signs and related symptoms. Many individuals with FHBL develop fatty liver or hepatic steatosis. In affected individuals more severely, fatty liver can progress to cirrhosis. In addition, individuals with severe FHBL have more difficulty absorbing fats and fat - soluble vitamins like vitamin E and vitamin A. This difficulty in absorbing fat leads to excess fat in the stool (steatorrhea). In childhood, these digestive problems can cause growth retardation.

This process is due in most cases to a deficiency of apolipoprotein B (apoB), caused by mutations in the gene encoding APOB. This gene, located on the short arm of chromosome 2 (2p24-p23) encodes two versions of apolipoprotein B: a short version called apolipoprotein B-48 and a longer version known as apolipoprotein B-100. Apolipoprotein B is a molecule which is the protein part of lipoproteins and allows blood lipid transport and exchange in different tissues. Specifically, apolipoprotein B-48 occurs in the intestine where it is essential for the formation of chylomicrons. Chylomicrons are also necessary for the absorption of certain fat - soluble vitamins such as vitamin E and vitamin A. The apolipoprotein B-100, is produced in the liver, where it is a component of several other types of lipoproteins. Specifically, this protein is a basic component of very low density lipoproteins (VLDL), intermediate density lipoprotein (IDL) and low density lipoproteins (LDL). Apolipoprotein B-100 allows these particles to bind specific receptors on the surface of cells, particularly in the liver. Receptors carrying low density lipoproteins in the cell, where they decompose to free cholesterol.

So far, we have identified more than 90 mutations in apoB gene in people affected family hypobetalipoproteinaemia (FHBL). These mutations result in proteins truncated ApoB can not form chylomicrons. The absence of these leads to accumulation of triglycerides in the enterocyte, making it impossible to process gradient causing its absorption from the intestinal lumen. Thus, it is generating intestinal absorption deficient with inability to transport fatty acids long chain, low density lipoprotein (LDL) and very low density (VLDL), most insoluble vitamins (A, K, E) and triglycerides synthesized in the liver, causing the symptoms described above.

Although mutations in the APOB gene are responsible for most cases of FHBL, mutations in other genes represent a small number of cases. These genes include ANGPTL3 gene, located on the short arm of chromosome 1 (1p31.3) and the PCSK9 gene, located on the short arm of chromosome 1 (1p32.3), which protein involved in the regulation of blood cholesterol. Mutations in the gene result ANGPTL3 family hypobetalipoproteinaemia type 2 (FHBL2) in which affected individuals have combined hypolipidemia, consisting of low levels of LDL cholesterol, HDL cholesterol and triglycerides in plasma. In some people with FHBL they have not identified mutations in these genes. It is likely that changes in other unidentified genes involved in the development of hypobetalipoproteinaemia.

The hypobetalipoproteinaemia is inherited in an autosomal codominant. Codominance means that two different versions of the gene are expressed, and both versions influence the genetic trait. In FHBL, a change in a copy of APOB gene in each cell may express the disease, but changes in both copies of the gene cause more serious problems.

Tests in IVAMI: in IVAMI perform detection of mutations associated with hypobetalipoproteinemia, by complete PCR amplification of the exons of ANGPTL3 APOB and genes, respectively, and subsequent sequencing. We recommend starting the study by the ApoB responsible for most cases, and continue gene, where appropriate, by the ANGPTL3 gene, saving time and cost accordingly.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).