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Functional Characterization and Classification of Frequent Low‐Density Lipoprotein Receptor Variants
Author(s) -
Etxebarria Aitor,
BenitoVicente Asier,
Palacios Lourdes,
Stef Marianne,
Cenarro Ana,
Civeira Fernando,
Ostolaza Helena,
Martin Cesar
Publication year - 2015
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22721
Subject(s) - ldl receptor , biology , familial hypercholesterolemia , genetics , phenotype , mutation , gene , receptor , low density lipoprotein , lipoprotein , cholesterol , endocrinology
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, LDLR mutations may be classified into five classes. The main objective of this study was to characterize seven LDLR variants 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. T rp577 G ly and p.Ile624del were classified as class 2, whereas p. A rg416 T rp and p. T hr454 A sn as class 5. p. P he800 G lyfs*129 (located in the cytoplasmic domain), p. C ys155 T yr (located in the binding domain), and p. A sn825 L ys (inside F x NP x Y 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. I le624del (class 2) compared with p. A rg416 T rp and p. T hr454 A sn (class 5) variants. In conclusion, these findings emphasize the importance of characterizing LDLR pathogenic variants to provide an indisputable FH diagnosis and to gain insight into the statin response depending on the LDLR class mutation.