Abstract
Familial hypobetalipoproteinemia (FHBL) is a codominant genetic disorder characterized by reduced plasma levels of low-density lipoprotein cholesterol and apolipoprotein B. To our knowledge, no study on FHBL in Lebanon and the Middle East region has been reported. Therefore, we conducted genetic studies in unrelated families and probands of Lebanese origin presenting with FHBL, in order to identify the causes of this disease. We found that 71% of the recruited probands and their affected relatives were heterozygous for the p.(Arg490Trp) variant in the APOB gene. Haplotype analysis showed that these patients presented the same mutant haplotype. Moreover, there was a decrease in plasma levels of PCSK9 in affected individuals compared to the non-affected and a significant positive correlation between circulating PCSK9 and ApoB levels in all studied probands and their family members. Some of the p.(Arg490Trp) carriers suffered from diabetes, hepatic steatosis or neurological problems. In conclusion, the p.(Arg490Trp) pathogenic variant seems a cause of FHBL in patients from Lebanese origin, accounting for approximately 70% of the probands with FHBL presumably as a result of a founder mutation in Lebanon. This study is crucial to guide the early diagnosis, management and prevention of the associated complications of this disease.
Highlights
Familial hypobetalipoproteinemia (FHBL1, OMIM #615558) is the most common monogenic form of primary hypobetalipoproteinemia [1,2]
This gene encodes the apolipoprotein B that exists in the plasma in two isoforms: ApoB-100 which is the full-length protein secreted by the liver and associated with the very-low-density lipoprotein (VLDL) and its metabolic products: intermediate-density lipoprotein (IDL) and LDL, and ApoB-48 which is the intestinal variant associated with chylomicrons
We highlight the presence of a pathogenic variant, p.(Arg490Trp), in exon 11 of the APOB gene, in several Lebanese families and probands presenting with FHBL, presumably because of a founder mutation
Summary
Familial hypobetalipoproteinemia (FHBL1, OMIM #615558) is the most common monogenic form of primary hypobetalipoproteinemia [1,2]. These mutations occur throughout the entire coding-region, mainly in exon 26, and are principally nucleotide substitutions (causing nonsense mutations) and deletions/insertions of a single or more nucleotides (causing frameshift mutations), and less commonly splice site mutations [3,4,14,15] These mutations interfere with the full translation of the protein by introducing a premature stop codon in ApoB mRNA and causing the synthesis of short truncated proteins of different sizes, ranging from ApoB-2 to ApoB-89, as per a centile nomenclature (percent length of the native ApoB-100 molecule) [3,4,12]. The first missense mutation is “p.(Arg490Trp) previously reported as p.(Arg463Trp)” (c.1468C>T, rs771541567) by Burnett et al in 2003 in an extended Lebanese family with FHBL living in Australia [16,17]
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