Familial hypobetalipoproteinemia: a review

Abstract

We review the genetics and pathophysiology of familial hypobetalipoproteinemia (FHBL), a mildly symptomatic genetically heterogeneous autosomal trait. The minority of human FHBL is caused by truncation-specifying mutations of the APOB gene on chromosome 2. In seven families, linkage to chromosome 2 is absent, linkage is instead to chromosome 3 (3p21). In others, linkage is absent to both APOB and to 3p21. Apolipoprotein B-100 (apoB-100) levels are ‫ف‬ 25% of normal, instead of the 50% expected based on the presence of one normal allele due to reduced rates of production. The presence of the truncating mutation seems to have a "dominant recessive" effect on apoB-100 secretion. Concentrations of apoB truncations in plasma differ by truncation but average at ‫ف‬ 10% of normal levels. Lipoproteins bearing truncated forms of apoB are cleared more rapidly than apoB-100 particles. In contrast with apoB-100 particles cleared primarily in liver via the LDL receptor, most apoB truncation particles are cleared in renal proximal tubular cells via megalin. Since apoB defects cause a dysfunctional VLDL-triglyceride transport system, livers accumulate fat. Hepatic synthesis of fatty acids is reduced in compensation. Informational lacunae remain about genes affecting fat accumulation in liver, and the modulation of liver fat in the presence apoB truncation defects. -Schonfeld, G.

Violent behavior associated with hypocholesterolemia due to a novel APOB gene mutation

“…14 Familial hypobetalipoproteinemia (FHBL) (OMIM 107730) is a codominant disorder of lipoprotein metabolism characterized by low levels ( < 5th percentile for age and sex) of LDL-cholesterol and apoB. 15,16 Over 50 mutations in the APOB gene, on chromosome 2, have been described to date, which either affect splicing or result in the production of truncated apoB isoforms. 17 Immunoblotting is the primary means for detecting truncated apoB isoforms in plasma.…”

Mea6 controls VLDL transport through the coordinated regulation of COPII assembly

“…VLDL synthesis is initiated in the endoplasmic reticulum (ER) of hepatocytes following the synthesis of the apolipoprotein (Apo) B100 and recruitment of TGs, cholesterol esters, and other apolipoproteins such as ApoE. ApoB mutations affect plasma lipid levels and are associated with familial hypobetalipoproteinemia disease [8]. Although more and more genes have been found to be involved in lipoprotein assembly and transport, and their disruption is associated with hepatic steatosis, the underlying mechanisms are still not very clear [9][10][11][12][13].…”

Missense Mutations in APOB within the βα1 Domain of Human APOB-100 Result in Impaired Secretion of ApoB and ApoB-containing Lipoproteins in Familial Hypobetalipoproteinemia

“…Heterozygotes are usually asymptomatic with LDL cholesterol and apoB-100 concentrations Ͻ50% of those in normal plasma. Homozygotes have undetectable plasma LDL cholesterol and apoB, and their clinical presentation, depending on the specific mutation, varies from no symptoms to severe gastrointestinal and neurological dysfunction, similar to that in abetalipoproteinemia (27,28,30). Nonsense, frameshift, and splicing mutations in the APOB gene leading to formation of prematurely truncated apoB species have been reported in FHBL subjects (27)(28)(29)(30).…”

“…Familial hypobetalipoproteinemia (FHBL; OMIM 107730) is a genetically heterogeneous autosomal co-dominant disorder characterized by low levels (Ͻ5th percentile for age and sex) of plasma apoB-containing lipoproteins (27)(28)(29)(30). It has been suggested that FHBL represents a longevity syndrome (31) and might be associated with cardiovascular protection because of resistance to atherosclerosis (32).…”