Spectrum of low density lipoprotein receptor mutations in Czech hypercholesterolemic patients

Kuhrová, Viera; Francová, Hana; Zapletalová, Petra; Freiberger, Tomáš; Fajkusová, Lenka; Hrabincová, Eva; Slováková, Romana; Kozák, Libor

doi:10.1002/humu.1185

Cited by 14 publications

(8 citation statements)

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“…Interestingly, one of the newly described mutations in this study (S285X) is caused by a substitution at a nucleotide position where other mutations have already been reported (Hobbs et al 1992;Schuster and Humphries 1994;Lombardi et al 1995;Pimstone et al 1997;Jensen et al 1999;Lombardi et al 2000;Kuhrova et al 2001Kuhrova et al , 2002. The mutation S285X identified in our study is caused by a substitution of cytosine by adenine (917C>A), whereas the two other substitutions at the same position identified earlier by other groups are another nonsense mutation 917C>G (Kuhrova et al 2001(Kuhrova et al , 2002, and a missense mutation 917C>T (S285L, known as FH Amsterdam) (Hobbs et al 1992;Schuster and Humphries 1994;Lombardi et al 1995;Pimstone et al 1997;Jensen et al 1999;Lombardi et al 2000).…”

Section: Resultssupporting

confidence: 56%

“…The mutation S285X identified in our study is caused by a substitution of cytosine by adenine (917C>A), whereas the two other substitutions at the same position identified earlier by other groups are another nonsense mutation 917C>G (Kuhrova et al 2001(Kuhrova et al , 2002, and a missense mutation 917C>T (S285L, known as FH Amsterdam) (Hobbs et al 1992;Schuster and Humphries 1994;Lombardi et al 1995;Pimstone et al 1997;Jensen et al 1999;Lombardi et al 2000). Consequently, nucleotide position 917 of LDLR can be described as a hot spot for point mutations causing FH.…”

Section: Resultssupporting

confidence: 46%

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Screening for point mutations in the LDL receptor gene in Bulgarian patients with severe hypercholesterolemia

et al. 2004

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Familial hypercholesterolemia (FH) is a common, autosomal dominant disorder of lipid metabolism, caused by defects in the receptor-mediated uptake of LDL (low-density lipoproteins) due to mutations in the LDL receptor gene (LDLR). Mutations underlying FH in Bulgaria are largely unknown. The aim of the present study was to provide information about the spectrum of point mutations in LDLR in a sample of 45 Bulgarian patients with severe hypercholesterolemia. Exons 3, 4, 6, 8, 9, and 14, previously shown to be mutational hot spots in LDLR, were screened using PCR-single-strand conformation polymorphism (SSCP). Samples with abnormal SSCP patterns were sequenced. Three different, hitherto undescribed point mutations (367T>A, 377T>A, 917C>A) and two previously described mutations (858C>A and 1301C>T) in eight unrelated patients were identified; four of the detected point mutations being missense mutations and one, a nonsense mutation. One of the newly described point mutations (917C>A) is a base substitution at a nucleotide position, at which two other different base substitutions have already been reported. Thus, all three possible base substitutions at this nucleotide position have been detected, making it a hot spot for point mutations causing FH. This is the first such mutational hot spot described in exon 6 of LDLR.

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Section: Resultssupporting

confidence: 56%

Section: Resultssupporting

confidence: 46%

Screening for point mutations in the LDL receptor gene in Bulgarian patients with severe hypercholesterolemia

et al. 2004

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“…Therefore, genetic screening strategies are mainly based on a first-line detection method, followed by DNA sequencing, in complement to Southern blotting. Mutations causing FH are usually detected by denaturing gradient gel electrophoresis (DGGE), single-strand conformation polymorphism (SSCP), or denaturing high performance liquid chromatography (Bertolini et al 2000;Bunn et al 2002;Ebhardt et al 1999;Ekström et al 1998;Graham et al 1999;Hattori et al 1999;Heath et al 2001;Jensen et al 1996;Kuhrova et al 2001;Lombardi et al 2000;Loux et al 1992;Mak et al 1998;Mozas et al 2000;Nauck et al 2001;Nissen et al 1996), and by DNA sequencing of polymerase chain reaction (PCR) products (Hobbs et al 1992;Leitersdorf et al 1990). In particular populations, oligonucleotide ligation assay (Baron et al 1996) and allele-specific oligonucleotides (Miltiadous et al 2001) have been used to detect known mutations.…”

Section: Introductionmentioning

confidence: 99%

Intronic mutations outside of Alu -repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia

et al. 2002

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Familial hypercholesterolemia (FH), a frequent monogenic condition complicated by premature cardiovascular disease, is characterized by high allelic heterogeneity at the low-density lipoprotein receptor ( LDLR) locus. Despite more than a decade of genetic testing, knowledge about intronic disease-causing mutations has remained limited because of lack of available genomic sequences. Based on the finding from bioinformatic analysis that Alu repeats represent 85% of LDLR intronic sequences outside exon-intron junctions, we designed a strategy to improve the exploration of genomic regions in the vicinity of exons in 110 FH subjects from an admixed population. In the first group of 42 patients of negative mutation carriers, as previously established by former screening strategies (denaturing gradient gel electrophoresis, DNA sequencing with former primers overlapping splice-sites, Southern Blotting), about half ( n=22) were found to be carriers of at least one heterozygous mutation. Among a second group of 68 newly recruited patients, 27% of mutation carriers ( n=37) had a splicing regulatory mutation. Overall, out of the 54 mutations identified, 13 were intronic, and 18 were novel, out of which nearly half were intronic. Two novel intronic mutations (IVS8-10G-->A within the polypyrimidine tract and IVS7+10G-->A downstream of donor site) might create potential aberrant splice sites according to neural-network computed estimation, contrary to 31 common single nucleotide variations also identified at exon-intron junctions. This new strategy of detecting the most likely disease-causing LDLR mutations outside of Alu-rich genomic regions reveals that intronic mutations may have a greater impact than previously reported on the molecular basis of FH.

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“…Scanning for unknown mutations causing FH has been done using DGGE, SSCP, or DHPLC [Bertolini et al, 2000;Bunn et al, 2002;Ebhardt et al, 1999;Ekström et al, 1995;Graham et al, 1999;Hattori et al, 1999;Heath et al, 2001;Kuhrova et al, 2001;Lombardi et al, 2000;Loux et al, 1992;Mak et al, 1998;Mozas et al, 2000;Nauck et al, 2001;Nissen et al, 1996], as well as DNA sequencing of PCR-amplified products [Hobbs et al, 1992;Leitersdorf et al, 1989]. In particular populations, oligonucleotide ligation assay [Baron et al, 1996] and allele-specific oligonucleotides [Miltiadous et al, 2001] have been used to detect known mutations.…”

Section: Criteria For Choosing a Screening Methodsmentioning

confidence: 99%

“…In the Czech Republic, 31 mutations were identified in a cohort of 352 unrelated hypercholesterolemic patients [Kuhrova et al, 2001]. The most frequent mutations are p.D266E [D245E] (14 patients; 4%) and c.1775G4A (p.G592E [G571E]) (10 patients; 2.8%).…”

Section: Fh In Central Europementioning

confidence: 99%

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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Spectrum of low density lipoprotein receptor mutations in Czech hypercholesterolemic patients

Abstract: The aim of our study was to define mutations causing familial hypercholesterolemia (

Cited by 14 publications

References 8 publications

Screening for point mutations in the LDL receptor gene in Bulgarian patients with severe hypercholesterolemia

Screening for point mutations in the LDL receptor gene in Bulgarian patients with severe hypercholesterolemia

Intronic mutations outside of Alu -repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia

LDL-receptor mutations in Europe

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