Familial hypercholesterolemia (FH) is an autosomal-dominant disorder mostly caused by mutations in the low-density lipoprotein receptor (LDLR) gene leading to increased risk for premature cardiovascular diseases. According to functional studies,LDLRmutations may be classified into five classes. The main objective of this study was to characterize sevenLDLRvariants previously detected in FH patients. Analysis by flow cytometry and confocal microscopy of LDLR activity demonstrate that all the studied variants are pathogenic. Among the mutations located in β-propeller, p.Trp577Gly and p.Ile624del were classified as class 2, whereas p.Arg416Trp and p.Thr454Asn as class 5. p.Phe800Glyfs*129 (located in the cytoplasmic domain), p.Cys155Tyr (located in the binding domain), and p.Asn825Lys (inside FxNPxY motif) were classified as class 2, 3, and 4, respectively. The results also show that LDLR activity of these class 4 and 5 variants is not completely abolished, showing a milder phenotype. We have also determined that statin response is more efficient lowering total cholesterol in heterozygous patients carrying p.Ile624del (class 2) compared with p.Arg416Trp and p.Thr454Asn (class 5) variants. In conclusion, these findings emphasize the importance of characterizingLDLRpathogenic variants to provide an indisputable FH diagnosis and to gain insight into the statin response depending on the LDLR class mutation.
Familial hypercholesterolemia (FH) is an autosomal-dominant disorder mostly caused by mutations in the LDLR leading to increased risk for premature cardiovascular diseases. In this study, we have characterized seven LDLR variants, previously found in FH patients. Among them, p.Trp577Gly, p.lle624del and p.Phe800Glyfs*129 were classified as class 2, p.Cys155Tyr as class 3, p.Asn825Lys as class 4 and, p.Arg416Trp and p. Thr454Asn as class 5. These findings emphasize the importance of characterizing LDLR pathogenic variants to provide an indisputable FH diagnosis.