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Functional analysis of LDLR promoter and 5′ UTR mutations in subjects with clinical diagnosis of familial hypercholesterolemia
Abstract
Familial hypercholesterolemia (FH) is a dominant disorder due to mutations in the LDLR gene. Several mutations in the LDLR promoter are associated with FH. Screening of 3,705 Spanish FH patients identified 10 variants in the promoter and 5' UTR. Here, we analyse the functionality of six newly identified LDLR variants. Mutations located in the LDLR promoter regulatory elements R2 and R3 (c.-155_-150delACCCCinsTTCTGCAAACTCCTCCC, c.-136C>G, c.-140C>G, and c.-140C>T) resulted in 6 to 15% residual activity in reporter expression experiments and changes in nuclear protein binding affinity compared to wild type. No reduction was observed when cells were transfected with c.-208T, c.-88A, and c.-36G mutant fragments. Our results indicate that mutations localized in R2 and R3 are associated with hypercholesterolemia, whereas mutations outside the LDLR response elements are not a cause of FH. This data emphasizes the importance of functional analysis of variants in the LDLR promoter to determine their association with the FH phenotype.
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Numerous mutations have been described in the LDLR promoter region that could impact SREBP-2 binding and LDLR transcriptional activation, leading to elevated cholesterol levels.
“Numerous mutations have been described in the promotor region which could impact the ability of SREBP-2 to bind LDLR and activate transcription of the gene leading to elevated cholesterol levels35–38.”
From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [36]
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Pathways and Molecular Mechanisms Governing LDL Receptor Regulation
Schmidt, H. M., Jarrett, K. E., de Aguiar Vallim, T. Q., & Tarling, E. J. (2025) · Circulation Research · doi:10.1161/circresaha.124.323578 · Cited by 33
Metadata
- Authors
- De Castro‐Orós, I., Pampín, S., Bolado‐Carrancio, A., De Cubas, A., Palacios, L., Plana, N., Puzo, J., Martorell, E., Stef, M., Masana, L., Civeira, F., Rodríguez‐Rey, J. C., & Pocoví, M.
- Affiliations
- Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Instituto Aragonés de Ciencias de la Salud (I + CS), Zaragoza, Spain
- Dpto. Biología Molecular, Facultad de Medicina, Universidad de Cantabria and Instituto de Formación e Investigación Marques de Valdecilla (IFIMAV), Santander, Spain
- Progenika Biopharma, S.A., Derio, Vizcaya, Spain
- Unitat de Medicina Vascular i Metabolisme (CIBERDEM), Universitat Rovira i Virgili, Reus, Spain
- Dpto. Bioquímica, Hospital San Jorge, Huesca, Spain
- Hospital Comarcal d'Inca, Islas Baleares, Spain
- RECAVA, Instituto de Salud Carlos III, Spain
- Venue
- Human Mutation
- Publisher
- Wiley
- Published
- 2011-07-12
- Volume
- 32
- Issue
- 8
- Pages
- 868-872
- ISSN
- 1059-7794
- 1098-1004
- Cited by
- 33
- References
- 0
- Language
- en
- Licence
- Funders
- Aragon Workers Health Study
- Grants from the Spanish Ministry of Health FIS (PS09/00665; PS09/00962; PS09/000673; RETIC RD06/0014/0029 (RECAVA))
- CIBERER
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