Characterization of a mutant form of human apolipoprotein B (Thr26_Tyr27del) associated with familial hypobetalipoproteinemia

In vitro functional characterization of splicing variants of the APOB gene found in familial hypobetalipoproteinemia

“…This missense variant might disrupt the intracellular transport of nascent apoB by promoting its rapid intracellular degradation, as it has been demonstrated for other missense variants located in the amino terminal end of apoB. [12][13][14][15] Taken together, our findings extend the list of ''pathogenic'' splicing variants of APOB gene found in subjects with homozygous and heterozygous FHBL-1. Cefal u et al 29 reviewed the APOB pathogenic variants identified in 18 FHBL-1 homozygotes and 13 compound heterozygotes reported in literature.…”

“…11 Single amino acid substitutions or minute in-frame deletions in apoB have been identified in FHBL-1 subjects and found to segregate with the hypobetalipoproteinemia trait in families. [12][13][14][15] These variants were found to impair the secretion of the mutant apoBs in transfected hepatic cells. These secretion-incompetent mutants are rapidly degraded intracellularly by various degradation pathways.…”

“…These secretion-incompetent mutants are rapidly degraded intracellularly by various degradation pathways. [12][13][14][15] A reduced postprandial production of TG-rich lipoproteins but normal postprandial clearance has also been demonstrated in FHBL-1 heterozygotes carrying the pathogenic missense variants R463W and L343V. 16,17 Genetic variants, which result in apoB truncations are predominantly due to single nucleotide substitutions resulting in premature termination codons, minute deletions/ insertions (causing frameshift with the occurrence of a premature termination codon), or, less frequently, to splicesite variants.…”

Lipids Responsible for Intestinal or Hepatic Disorder

“…Heterozygous carriers of a truncated ApoB are often asymptomatic, but may develop a fatty liver due to a reduced capacity to bind lipids and form mature lipoproteins in the liver or intestine, and from a compromised ability to export lipids from these organs (9,13).…”

“…FHBL is the most frequent familial intestinal hypocholesterolemia, and has autosomal codominant inheritance; however, homozygous FHBL is rare (1 in 1 million) and is characterised by extremely low or undetectable plasma levels of LDL‐C (13).…”