The two sides of a coin: Pathogenicity and potential therapeutic of LDLRQ722*

Abstract

Abstract Familial hypercholesterolemia (FH) is a severe inherited lipid metabolism dysfunction, characterized by high low‐density lipoprotein (LDL) cholesterol levels, mostly due to mutations in the LDL receptor (LDLR) gene. Whole exome sequencing was performed on a consanguineous Chinese FH family and identified a novel homozygous pathogenic mutation LDLR c.C2164T (p. Q722*), forming a novel truncated soluble LDLRQ722*. LDLRQ722* was secreted via the small extracellular vesicles (sEV) and located on the surface of sEV. LDLRQ722*exhibit ∼6% of the wild‐type LDLR activity. sEV containing LDLRQ722* protein reconstructed the lipid metabolism via heparan sulfate proteoglycans (HSPG) and clathrin‐mediated endocytosis. Currently, statins and PCSK9 inhibitors therapy are the mainstay treatment for FH. However, statins and PCSK9 inhibitors substantially vary depending on the residual LDLR activity, while LDLRQ722* reduced circulating LDL‐C levels independently of LDLR residual activity. The study provided new insight into the treatments of FH.

Keywords

• familial hypercholesterolemia
• small extracellular vesicle
• soluble truncated LDLR