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Functional analysis of LDLR promoter and 5′ UTR mutations in subjects with clinical diagnosis of familial hypercholesterolemia

✍ Scribed by Isabel De Castro-Orós; Sandra Pampín; Alfonso Bolado-Carrancio; Aguirre De Cubas; Lourdes Palacios; Nuria Plana; Jose Puzo; Esperanza Martorell; Marianne Stef; Luis Masana; Fernando Civeira; Jose Carlos Rodríguez-Rey; Miguel Pocoví

Publisher
John Wiley and Sons
Year
2011
Tongue
English
Weight
252 KB
Volume
32
Category
Article
ISSN
1059-7794

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✦ Synopsis

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 0 UTR. Here, we analyse the functionality of six newly identified LDLR variants. Mutations located in the LDLR promoter regulatory elements R2 and R3 (c.À155_-150delACCCCinsTTCTG-CAAACTCCTCCC, c.À136C4G, c.À140C4G, and c.À140C4T) 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.À208T, c.À88A, and c.À36G 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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