Genetic analysis of a kindred with familial hypobetalipoproteinemia. Evidence for two separate gene defects: one associated with an abnormal apolipoprotein B species, apolipoprotein B-37; and a second associated with low plasma concentrations of apolipoprotein B-100.
We report the presence of two distinct defects of the gene for apolipoprotein B, one resulting in a new truncated variant, apoB-61, in a kindred with familial hypobetalipoproteinemia (FHB).
More than 20 different mutations in the apoB gene have been shown to cause familial hypobetalipoproteinaemia, a condition characterized by abnormally low plasma concentrations of apoB and LDL cholesterol.
Thus, a single nucleotide transversion in the apoB gene results in a unique truncated apoB species, apoB-83, and the clinical syndrome of familial hypobetalipoproteinemia.
Familial hypobetalipoproteinemia represents a heterogeneous group of genetic defects in which the concentrations of plasma apolipoprotein B and apo-B-containing lipoproteins VLDL and LDL are abnormally low.
Familial hypobetalipoproteinemia is caused by apolipoprotein (apo) B gene mutations and is frequently associated with a truncated apo-B protein in the plasma.
We believe these reduced production rates largely account for the lower than expected levels of apoB-100 and LDL cholesterol in the plasma of FHBL heterozygotes.
The purpose of this study was to characterize intestinal apolipoprotein B (apoB) metabolism in subjects with familial hypobetalipoproteinemia (FHBL), where segregation analysis supports linkage to the apoB gene but no apoB truncations are present.
These studies have helped in 1) generating new mouse models suitable for investigating the genetic and environmental factors affecting atherogenesis; 2) providing systems for investigating apoB structure/function relationships; 3) understanding the regulation of apoB gene expression in the intestine; 4) delineating a critical role for apoB expression in mouse embryonic development; 5) yielding insights into the "physiologic rationale" for the existence of the two different forms of apoB, apoB-48 and apoB-100, in mammalian metabolism; and 6) providing basic insights into mechanisms involved in the human apoB deficiency syndrome, familial hypobetalipoproteinemia.
In subjects with familial hypobetalipoproteinemia heterozygous for truncated forms of apolipoprotein B, both apoB-100 and the truncated forms are produced at lower than expected rates.