Functional studies of APOB variants the experience of the Portuguese Familial Hypercholesterolemia Study

Ferreira, Maria Simões; Chora, Joana Rita; Medeiros, Ana Margarida; Bourbon, Mafalda; Alves, Ana Catarina

http://hdl.handle.net/10400.18/8862

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Authors

Ferreira, Maria Simões

Chora, Joana Rita

Medeiros, Ana Margarida

Bourbon, Mafalda

Alves, Ana Catarina

Abstract(s)

Familial hypercholesterolemia (FH) is clinically characterized by increased levels of circulating LDL cholesterol leading to premature coronary heart disease. It can be caused by variants in LDLR, APOB, and PCSK9 genes. APOB variants are responsible for 5-10% of the FH cases, p.(Arg3527Gln) being the most common. Only recently the whole gene has been sequenced due to Next Generation Sequencing, increasing the variant spectrum of APOB and with it the number of variants that need to be functionally assessed. We aimed to characterize novel APOB variants identified in patients included in the Portuguese FH Study to confirm if they are the genetic cause of hypercholesterolemia. To better analyze these variants, we also create a database with all APOB rare variants found up to date in the Portuguese FH Study. The functional study of 5 variants is ongoing. To access if these variants affect apoB:LDL receptor binding, LDL from index cases and relatives with the variants was separated using sequential ultracentrifugation, and proliferation assays were performed with U937 cells. These cells do not synthesize cholesterol and they depend on apoB:LDL receptor binding to grow.