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. Epub 2020 Dec 14.


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.

Keywords: cardiovascular disease; genetics; lipids; microRNA; polyadenylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Alternative Splicing
  • Cholesterol, LDL / blood*
  • Gain of Function Mutation
  • Gene Deletion
  • Genetic Vectors / genetics
  • Genetic Vectors / metabolism
  • Herpesvirus 4, Human / genetics
  • Heterozygote
  • Humans
  • Hyperlipoproteinemia Type II / genetics
  • Hyperlipoproteinemia Type II / pathology
  • Iceland
  • Lymphocytes / cytology
  • Lymphocytes / metabolism
  • MicroRNAs / metabolism
  • Pedigree
  • Protein Isoforms / genetics
  • RNA, Messenger / metabolism
  • Receptors, LDL / genetics*


  • 3' Untranslated Regions
  • Cholesterol, LDL
  • LDLR protein, human
  • MicroRNAs
  • Protein Isoforms
  • RNA, Messenger
  • Receptors, LDL