TY - JOUR
T1 - Identification of a loss-of-function inducible degrader of the low-density lipoprotein receptor variant in individuals with low circulating low-density lipoprotein
AU - Sorrentino, Vincenzo
AU - Fouchier, Sigrid W.
AU - Motazacker, Mohammad M.
AU - Nelson, Jessica K.
AU - Defesche, Joep C.
AU - Dallinga-Thie, Geesje M.
AU - Kastelein, John J. P.
AU - Kees Hovingh, G.
AU - Zelcer, Noam
PY - 2013
Y1 - 2013
N2 - Recent genome-wide association studies suggest that IDOL (also known as MYLIP) contributes to variation in circulating levels of low-density lipoprotein cholesterol (LDL-C). IDOL, an E3-ubiquitin ligase, is a recently identified post-transcriptional regulator of LDLR abundance. Briefly, IDOL promotes degradation of the LDLR thereby limiting LDL uptake. Yet the exact role of IDOL in human lipoprotein metabolism is unclear. Therefore, this study aimed at identifying and functionally characterizing IDOL variants in the Dutch population and to assess their contribution to circulating levels of LDL-C. We sequenced the IDOL coding region in 677 individuals with LDL-C above the 95th percentile adjusted for age and gender (high-LDL-C cohort) in which no mutations in the LDLR, APOB, and PCSK9 could be identified. In addition, IDOL was sequenced in 560 individuals with baseline LDL-C levels below the 20th percentile adjusted for age and gender (low-LDL-C cohort). We identified a total of 14 IDOL variants (5 synonymous, 8 non-synonymous, and 1 non-sense). Functional characterization of these variants demonstrated that the p.Arg266X variant represents a complete loss of IDOL function unable to promote ubiquitylation and subsequent degradation of the LDLR. Consistent with loss of IDOL function, this variant was identified in individuals with low circulating LDL-C. Our results support the notion that IDOL contributes to variation in circulating levels of LDL-C. Strategies to inhibit IDOL activity may therefore provide a novel therapeutic venue to treating dyslipidaemia
AB - Recent genome-wide association studies suggest that IDOL (also known as MYLIP) contributes to variation in circulating levels of low-density lipoprotein cholesterol (LDL-C). IDOL, an E3-ubiquitin ligase, is a recently identified post-transcriptional regulator of LDLR abundance. Briefly, IDOL promotes degradation of the LDLR thereby limiting LDL uptake. Yet the exact role of IDOL in human lipoprotein metabolism is unclear. Therefore, this study aimed at identifying and functionally characterizing IDOL variants in the Dutch population and to assess their contribution to circulating levels of LDL-C. We sequenced the IDOL coding region in 677 individuals with LDL-C above the 95th percentile adjusted for age and gender (high-LDL-C cohort) in which no mutations in the LDLR, APOB, and PCSK9 could be identified. In addition, IDOL was sequenced in 560 individuals with baseline LDL-C levels below the 20th percentile adjusted for age and gender (low-LDL-C cohort). We identified a total of 14 IDOL variants (5 synonymous, 8 non-synonymous, and 1 non-sense). Functional characterization of these variants demonstrated that the p.Arg266X variant represents a complete loss of IDOL function unable to promote ubiquitylation and subsequent degradation of the LDLR. Consistent with loss of IDOL function, this variant was identified in individuals with low circulating LDL-C. Our results support the notion that IDOL contributes to variation in circulating levels of LDL-C. Strategies to inhibit IDOL activity may therefore provide a novel therapeutic venue to treating dyslipidaemia
U2 - https://doi.org/10.1093/eurheartj/ehs472
DO - https://doi.org/10.1093/eurheartj/ehs472
M3 - Article
C2 - 23324548
SN - 0195-668X
VL - 34
SP - 1292
EP - 1297
JO - European Heart journal
JF - European Heart journal
IS - 17
ER -