FH‐Pyrgos: a novel mutation in the promoter (−45delT) of the low‐density lipoprotein receptor gene associated with familial hypercholesterolemia

Dedoussis, George; Pitsavos, C.; Kelberman, Daniel; Skoumas, John; Prassa, Margarita; Choumerianou, Despoina M.; Stefanadis, Christodoulos; Humphries, Steve E.; Toutouzas, Pavlos

doi:10.1034/j.1399-0004.2003.00164.x

Cited by 16 publications

(13 citation statements)

References 11 publications

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“…Large rearrangements and deletions, and frameshift and nonsense mutations resulting in truncated proteins are obviously pathogenic; however, the pathogenicity of missense mutations is often uncertain. Furthermore, mutations situated in the promoter region, in splice-site junctions and the untranslated 3 0 -region should be critically evaluated through studies of mRNA alterations [Jensen et al, 1996c[Jensen et al, , 1996dDedoussis et al, 2003].…”

Section: Criteria For Choosing a Screening Methodsmentioning

confidence: 99%

“…Accordingly, six different mutations in repeat 3 that emerge to FH phenotypes have been described. [Sun et al, 1995b;Dedoussis et al, 2003], and c.1-142C4T [-49] [Mozas et al, 2002], all within the 10-bp sequence ACTCCTCCCC (coordinates À143 to À134), which resembles the consensus GC box sequence identified as the Sp1 binding site [Kadonaga et al, 1986]. A homozygous substitution, c.1-156C4T [À63C4T] in the repeat 2 domain of the promoter region has recently been described by our group [Dedoussis et al, 2004] in a FH patient of Jordanian origin.…”

Section: Promoter Mutationsmentioning

confidence: 96%

“…Major rearrangements (n=79) account for 10% of all mutations and in the majority of them result from unequal recombination between the 30 Alu sequences identified throughout the gene [Hobbs et al, 1990]. Only nine mutations (1%) have been found in the promoter [Dedoussis et al, 2003[Dedoussis et al, , 2004. Large deletions account for approximately 7% of all mutations of the LDLR gene [Horsthemke et al, 1987;Sun et al, 1992].…”

Section: Ldl Receptor Deficiencymentioning

confidence: 98%

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LDL-receptor mutations in Europe

2004

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Familial hypercholesterolemia (FH) is a clinical definition for a remarkable increase of cholesterol serum concentration, presence of xanthomas, and an autosomal dominant trait of either increased serum cholesterol or premature coronary artery disease (CAD). The identification of the low-density lipoprotein (LDL)-receptor (LDLR) as the underlying cause and its genetic characterization in FH patients revealed more insights in the trafficking of LDL, which primarily transports cholesterol to hepatic and peripheral cells. Mutations within LDLR result in hypercholesterolemia and, subsequently, cholesterol deposition in humans to a variable degree. This confirms the pathogenetic role of LDLR and also highlights the existence of additional factors in determining the phenotype. Autosomal dominant FH is caused by LDLR deficiency and defective apolipoprotein B-100 (APOB), respectively. Heterozygosity of the LDLR is relatively common (1:500). Clinical diagnosis is highly important and genetic diagnosis may be helpful, since treatment is usually effective for this otherwise fatal disease. Very recently, mutations in PCSK9 have been also shown to cause autosomal dominant hypercholesterolemia. For autosomal recessive hypercholesterolemia, mutations within the so-called ARH gene encoding a cellular adaptor protein required for LDL transport have been identified. These insights emphasize the crucial importance of LDL metabolism intra- and extracellularly in determining LDL-cholesterol serum concentration. Herein, we focus on the published European LDLR mutation data that reflect its heterogeneity and phenotypic penetrance.

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Section: Criteria For Choosing a Screening Methodsmentioning

confidence: 99%

Section: Promoter Mutationsmentioning

confidence: 96%

Section: Ldl Receptor Deficiencymentioning

confidence: 98%

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LDL-receptor mutations in Europe

2004

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“…As a positive control, transfection was carried out using the equivalent wild-type pGL3 construct, and as negative controls, two constructs previously reported to diminish promoter activity: À138T4C 6 and À138delT. 5 Transfection of the À139C4G-carrying construct demonstrated a 74% (71.4% SEM) reduced mean level of luciferase activity in Huh7 cells, compared to the wild-type construct, and comparable to the levels produced by both LDLR-138 variants (T4C: 3.2-fold70.6% SEM; delT: 3.7-fold70.5% SEM reduction in luciferase activity compared to wild-type construct).…”

Section: Luciferase Reporter Assaymentioning

confidence: 99%

“…5 Using the QuickChange Site-Directed Mutagenesis kit (Stratagene, La Jolla, CA, USA) as directed, a C4G mutation was created at position À139 (mutagenesis primers available on request). The 595 bp fragment was sub-cloned into WT pGL3 plasmid, and the mutation verified by direct sequencing using the DYEnamic Dye Terminator kit protocol (GE Healthcare, Buckinghamshire, UK) on the MegaBACE 1000 (GE Healthcare).…”

Section: Mutagenesis Of Ldlr Reporter Plasmidmentioning

confidence: 99%

A functional mutation in the LDLR promoter (−139C>G) in a patient with familial hypercholesterolemia

et al. 2007

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A novel sequence change in repeat 3 of the promoter of the low-density lipoprotein receptor (LDLR) gene, À139C4G, has been identified in a patient with familial hypercholesterolemia (FH). LDLR -139G has been passed to one offspring who also shows an FH phenotype. Transient transfection studies using luciferase gene reporter assays revealed a considerable reduction (7471.4% SEM) in reporter gene expression from the À139G variant sequence compared to the wild-type sequence, strongly suggesting that this change is the basis for FH in these patients. Analysis using electrophoretic mobility shift assay demonstrated the loss of Sp1 binding to the variant sequence in vitro, explaining the reduction of transcription.

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

et al. 2011

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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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FH‐Pyrgos: a novel mutation in the promoter (−45delT) of the low‐density lipoprotein receptor gene associated with familial hypercholesterolemia

Cited by 16 publications

References 11 publications

LDL-receptor mutations in Europe

LDL-receptor mutations in Europe

A functional mutation in the LDLR promoter (−139C>G) in a patient with familial hypercholesterolemia

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

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