Lifelong Reduction in LDL (Low-Density Lipoprotein) Cholesterol due to a Gain-of-Function Mutation in LDLR
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Halldorsson, Gisli H
Arnadottir, Gudny A
Olafsdottir, Eva F
Eyjolfsson, Gudmundur I
Magnusson, Olafur Th
Gudbjartsson, Daniel F
Halldorsson, Bjarni V
Norddahl, Gudmundur L
MetadataShow full item record
CitationBjornsson E, Gunnarsdottir K, Halldorsson GH, Sigurdsson A, Arnadottir GA, Jonsson H, Olafsdottir EF, Niehus S, Kehr B, Sveinbjörnsson G, Gudmundsdottir S, Helgadottir A, Andersen K, Thorleifsson G, Eyjolfsson GI, Olafsson I, Sigurdardottir O, Saemundsdottir J, Jonsdottir I, Magnusson OT, Masson G, Stefansson H, Gudbjartsson DF, Thorgeirsson G, Holm H, Halldorsson BV, Melsted P, Norddahl GL, Sulem P, Thorsteinsdottir U, Stefansson K. Lifelong Reduction in LDL (Low-Density Lipoprotein) Cholesterol due to a Gain-of-Function Mutation in LDLR. Circ Genom Precis Med. 2021 Feb;14(1):e003029. doi: 10.1161/CIRCGEN.120.003029.
AbstractBackground: Loss-of-function mutations in the LDL (low-density lipoprotein) receptor gene (LDLR) cause elevated levels of LDL cholesterol and premature cardiovascular disease. To date, a gain-of-function mutation in LDLR with a large effect on LDL cholesterol levels has not been described. Here, we searched for sequence variants in LDLR that have a large effect on LDL cholesterol levels. Methods: We analyzed whole-genome sequencing data from 43 202 Icelanders. Single-nucleotide polymorphisms and structural variants including deletions, insertions, and duplications were genotyped using whole-genome sequencing-based data. LDL cholesterol associations were carried out in a sample of >100 000 Icelanders with genetic information (imputed or whole-genome sequencing). Molecular analyses were performed using RNA sequencing and protein expression assays in Epstein-Barr virus-transformed lymphocytes. Results: We discovered a 2.5-kb deletion (del2.5) overlapping the 3' untranslated region of LDLR in 7 heterozygous carriers from a single family. Mean level of LDL cholesterol was 74% lower in del2.5 carriers than in 101 851 noncarriers, a difference of 2.48 mmol/L (96 mg/dL; P=8.4×10-8). Del2.5 results in production of an alternative mRNA isoform with a truncated 3' untranslated region. The truncation leads to a loss of target sites for microRNAs known to repress translation of LDLR. In Epstein-Barr virus-transformed lymphocytes derived from del2.5 carriers, expression of alternative mRNA isoform was 1.84-fold higher than the wild-type isoform (P=0.0013), and there was 1.79-fold higher surface expression of the LDL receptor than in noncarriers (P=0.0086). We did not find a highly penetrant detrimental impact of lifelong very low levels of LDL cholesterol due to del2.5 on health of the carriers. Conclusions: Del2.5 is the first reported gain-of-function mutation in LDLR causing a large reduction in LDL cholesterol. These data point to a role for alternative polyadenylation of LDLR mRNA as a potent regulator of LDL receptor expression in humans. Keywords: cardiovascular disease; genetics; lipids; microRNA; polyadenylation.
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