ArticleEuropean journal of human genetics : EJHG2015
Functional analysis of four LDLR 5'UTR and promoter variants in patients with familial hypercholesterolaemia.
Article in European journal of human genetics : EJHG, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 29 citations in OpenAlex.
- Novel start codon variant in the 5'UTR of LDLR associated with familial hypercholesterolaemia.European journal of human genetics : EJHG · 2026Article
- Functional interrogation of candidate cis-regulatory elements at the LDLR locus.PLoS genetics · 2026Article
- Investigation of the Effects of NoncodingHuman heredity · 2026Article
- Beyond the Exome: The Role of Noncoding and Regulatory Variants in Monogenic Diseases.Current issues in molecular biology · 2025Review
- uAUG-creating variant in the LDLR gene causes mild Familial hypercholesterolemia.Human genetics · 2025Article
- Predicting functional constraints across evolutionary timescales with phylogeny-informed genomic language models.bioRxiv : the preprint server for biology · 2025Article
- Pathways and Molecular Mechanisms Governing LDL Receptor Regulation.Circulation research · 2025Review
- Familial hypercholesterolemia - Targeted whole gene sequencing as a diagnostic approach.Atherosclerosis plus · 2025Article
- LMX1B haploinsufficiency due to variants in the 5'UTR as a cause of Nail-Patella syndrome.NPJ genomic medicine · 2025Article
- Functional Analysis of 3'UTR Variants at theHuman mutation · 2024Article
- Calling and Phasing of Single-Nucleotide and Structural Variants of theInternational journal of molecular sciences · 2023Article
- Common and Rare 5'UTR Variants Altering Upstream Open Reading Frames in Cardiovascular Genomics.Frontiers in cardiovascular medicine · 2022Review
- Genetic testing for familial hypercholesterolemia-past, present, and future.Journal of lipid research · 2021Review
- Variants in the 5'UTR reduce SHOX expression and contribute to SHOX haploinsufficiency.European journal of human genetics : EJHG · 2021Article
- Article
- The UCL low-density lipoprotein receptor gene variant database: pathogenicity update.Journal of medical genetics · 2017Article
- Article
- The importance of an integrated analysis of clinical, molecular, and functional data for the genetic diagnosis of familial hypercholesterolemia.Genetics in medicine : official journal of the American College of Medical Genetics · 2015Article
- Association study of genetic variants at newly identified lipid gene TRIB1 with coronary heart disease in Chinese Han population.Lipids in health and disease · 2015Article
- Use of targeted exome sequencing as a diagnostic tool for Familial Hypercholesterolaemia.Journal of medical genetics · 2012Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Familial hypercholesterolaemia (FH) is an autosomal dominant inherited disease characterised by increased low-density lipoprotein cholesterol (LDL-C) levels. The functionality of four novel variants within the LDLR 5'UTR and promoter located at c.-13A>G, c.-101T>C, c.-121T>C and c.-215A>G was investigated using in silico and in vitro assays, and a systemic bioinformatics analysis of all 36 reported promoter variants are presented. Bioinformatic tools predicted that all four variants occurred in sites likely to bind transcription factors and that binding was altered by the variant allele. Luciferase assay was performed for all the variants. Compared with wild type, the c.-101T>C and c.-121T>C variants showed significantly lower mean (±SD) luciferase activity (64 ± 8 and 72 ± 8%, all P<0.001), suggesting that these variants are causal of the FH phenotype. No significant effect on gene expression was seen for the c.-13A>G or c.-215A>G variants (96 ± 15 and 100 ± 12%), suggesting these variants are not FH causing. Similar results were seen for the c.-101T>C and c.-121T>C variants in lipid-depleted serum. However, a significant reduction in luciferase activity was seen in the c.-215A>G variant in lipid-depleted serum. Electrophoretic-mobility shift assays identified allele-specific binding of liver (hepatoma) nuclear proteins to c.-121T>C and suggestive differential binding to c.-101T>C but no binding to c.-215A>G. These data highlight the importance of in vitro testing of reported LDLR promoter variants to establish their role in FH. The functional assays performed suggest that the c.-101T>C and c.-121T>C variants are pathogenic, whereas c.-13A>G variant is benign, and the status of c.-215A>G remains unclear.
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