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Functional analysis of LDLR promoter and 5′ UTR mutations in subjects with clinical diagnosis of familial hypercholesterolemia
Author(s) -
De CastroOrós Isabel,
Pampín Sandra,
BoladoCarrancio Alfonso,
De Cubas Aguirre,
Palacios Lourdes,
Plauria,
Puzo Jose,
Martorell Esperanza,
Stef Marianne,
Masana Luis,
Civeira Fernando,
RodríguezRey Jose Carlos,
Pocoví Miguel
Publication year - 2011
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21520
Subject(s) - ldl receptor , familial hypercholesterolemia , biology , genetics , mutant , phenotype , mutation , gene , microbiology and biotechnology , promoter , untranslated region , gene expression , messenger rna , cholesterol , endocrinology , lipoprotein
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.Hum Mutat 32:1–5, 2011. © 2011 Wiley‐Liss, Inc.