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Cited by 23

The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.

Lifelong Reduction in LDL (Low-Density Lipoprotein) Cholesterol due to a Gain-of-Function Mutation in LDLR

Bjornsson, Eythor, Gunnarsdottir, Kristbjorg, Halldorsson, Gisli H., Sigurdsson, Asgeir, Arnadottir, Gudny A., Jonsson, Hakon, Olafsdottir, Eva F., Niehus, Sebastian, Kehr, Birte, Sveinbjörnsson, Gardar, Gudmundsdottir, Steinunn, Helgadottir, Anna, Andersen, Karl, Thorleifsson, Gudmar, Eyjolfsson, Gudmundur I., Olafsson, Isleifur, Sigurdardottir, Olof, Saemundsdottir, Jona, Jonsdottir, Ingileif, Magnusson, Olafur Th., Masson, Gisli, Stefansson, Hreinn, Gudbjartsson, Daniel F., Thorgeirsson, Gudmundur, Holm, Hilma, Halldorsson, Bjarni V., Melsted, Pall, Norddahl, Gudmundur L., Sulem, Patrick, Thorsteinsdottir, Unnur, Stefansson, Kari·2021·Circulation: Genomic and Precision Medicine
DOI 10.1161/circgen.120.003029
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Abstract

Background: 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.

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Crossref · 10.1161/circgen.120.003029

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6 of 6 references verified0 citation errors · 0 not checkable

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  • The increase in hepatic LDLR and decrease in plasma LDL-C after treatment with ASO is comparable to a recently reported gain-of-function mutation in LDLR, which caused a 74% decrease in LDL-C in humans.

    “The increase in hepatic LDLR and decrease in plasma LDL-C after treatment with ASO is comparable to a recently reported gain-of-function mutation in LDLR46, which caused a 74% decrease in LDL-C in humans.”

    From RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels (2023) · cites this paper as [46]

  • Observed changes in LDLR expression and circulating LDL were not attributed to loss of specific binding sites for a particular miRNA or RBP.

    “Observed changes in LDLR expression and circulating LDL were not attributed to loss of specific binding sites for a particular miRNA or RBP67.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [67]

  • The truncated 3'UTR lacks binding sites for both miR128-1 and miR-148, while the miR-185 binding site is still present.

    “This truncated 3’UTR lacks binding sites for both miR128-1 and miR-14852,53,67, while the miR-185 binding site is still present54,67.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [67]

  • Bjornsson et al. identified an Icelandic family with a gain of function mutation in LDLR that correlated with dramatically lower levels of circulating LDL.

    “Recently, Bjornsson et. al. identified an Icelandic family with a gain of function mutation in LDLR that correlated with dramatically lower levels of circulating LDL levels67.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [67]

  • In screening 43,202 Icelanders for mutations in LDLR that resulted in improved LDL levels, a rare 2.5 kilobase deletion at the end of the 3'UTR was identified across several generations of the same family.

    “In screening 43,202 Icelanders for mutations in LDLR that resulted in improved LDL levels, a rare 2.5 kilobase deletion at the end of the 3’UTR was identified across several generations of the same family67.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [67]

Citations

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Metadata

Authors
Bjornsson, E., Gunnarsdottir, K., Halldorsson, G. H., Sigurdsson, A., Arnadottir, G. A., Jonsson, H., Olafsdottir, E. F., Niehus, S., Kehr, B., Sveinbjörnsson, G., Gudmundsdottir, S., Helgadottir, A., Andersen, K., Thorleifsson, G., Eyjolfsson, G. I., Olafsson, I., Sigurdardottir, O., Saemundsdottir, J., Jonsdottir, I., Magnusson, O. T., Masson, G., Stefansson, H., Gudbjartsson, D. F., Thorgeirsson, G., Holm, H., Halldorsson, B. V., Melsted, P., Norddahl, G. L., Sulem, P., Thorsteinsdottir, U., & Stefansson, K.
Affiliations
  • deCODE genetics/Amgen, Inc (E.B., K.G., G.H.H., A.S., G.A.A., H.J., G.S., S.G., A.H., G. Thorleifsson, J.S., I.J., O.T.M., G.M., H.S., D.F.G., G. Thorgeirsson, H.H., B.V.H., P.M., G.L.N., P.S., U.T., K.S.), University of Iceland.
  • Department of Internal Medicine (E.B., E.F.O.), Division of Cardiology, Department of Internal Medicine (K.A., G. Thorgeirsson), Landspítali - The National University Hospital of Iceland, Reykjavík.
  • Berlin Institute of Health (S.N., B.K.), Humboldt-Universität zu Berlin &amp; Berlin Institute of Health, Berlin, Germany.
  • Faculty of Medicine (E.B., K.A., I.J., U.T., K.S.), University of Iceland.
  • The Laboratory in Mjódd, Reykjavík (G.I.E.).
  • Department of Clinical Biochemistry (I.O.), Landspítali - The National University Hospital of Iceland, Reykjavík.
  • Department of Clinical Biochemistry, Akureyri Hospital (O.S.).
ORCID
Venue
Circulation: Genomic and Precision Medicine
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2021-02
Volume
14
Issue
1
ISSN
2574-8300
DOI
10.1161/circgen.120.003029
Cited by
23
References
6
Language
en

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