Identification of a Variant in APOB Gene as a Major Cause of Hypobetalipoproteinemia in Lebanese Families

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.

Low circulating PCSK9 levels in LPL homozygous children with chylomicronemia syndrome in a syrian refugee family in Lebanon

“…It is suggested that this correlation is due to the fact that PCSK9 acts as an important regulator of LDL metabolism through targeting the LDLR for lysosomal degradation, but also due to a direct interaction between PCSK9 and LDL (Abifadel et al, 2010;Tavori et al, 2015). Further studies of PCSK9 levels in patients with hyperchylomicronemia would be interesting in order to verify if all homozygous patients with T1HLP have low PCSK9 levels, or if it is specific to the patients in the studied family, and to decipher the causes of this decrease, as well as the mechanism, the role of PCSK9, and its correlation with ApoB levels (Ayoub et al, 2021).…”

The genetics of monogenic intestinal epithelial disorders

“…Disease-associated mutations in APOB are largely composed of truncations, splice variants, and nonsense mutations. Only one missense mutation has been identified, p.Arg463Trp, which was originally reported as “p.Arg490Trp” when first described in 2003 (Hooper et al 2005 ; Ayoub et al 2021 ). This mutation is found primarily in individuals of Lebanese descent (Ayoub et al 2021 ).…”

“…Only one missense mutation has been identified, p.Arg463Trp, which was originally reported as “p.Arg490Trp” when first described in 2003 (Hooper et al 2005 ; Ayoub et al 2021 ). This mutation is found primarily in individuals of Lebanese descent (Ayoub et al 2021 ). The exact mechanism by which it induces HHBL remains unclear.…”