Background
- Loss-of-function mutations in the LDL 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 sequence (WGS) data from 43,202 Icelanders. Single-nucleotide polymorphisms and structural variants including deletions, insertions and duplications were genotyped using WGS-based data. LDL cholesterol associations were carried out in a sample of >100,000 Icelanders with genetic information (imputed or WGS). 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 (UTR) of
LDLR
in seven heterozygous carriers from a single family. Mean level of LDL cholesterol was 74% lower in del2.5 carriers than in 101,851 non-carriers, 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' UTR. 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 non-carriers (
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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