Sequencing of the coding exons of the LRP1 and LDLR genes on individual DNA samples reveals novel mutations in both genes

Leuven, Fred Van; Thiry, Els; Lambrechts, Marie-Claire; Stas, Lou; Boon, Thierry; Bruynseels, Koen; Muls, Erik; Descamps, Olivier

doi:10.1016/s0021-9150(00)00657-2

Cited by 18 publications

(12 citation statements)

References 45 publications

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“…For example, the peak on chromosome 12 is near the location of the gene encoding the LDL lipoprotein receptor-related protein (28). LRP is a 600 kDa cell surface receptor expressed in a variety of tissues, including hepatocytes (29). LRP shows homology to the LDL receptor, but is considered more complex in structure and function, containing 31 ligand binding-type repeats, as compared with the seven found in the LDL receptor (22).…”

Section: Discussionmentioning

confidence: 99%

Lack of genetic linkage evidence for a trans-acting factor having a large effect on plasma lipoprotein[a] levels in African Americans

Barkley

Brown

Hanis

et al. 2003

Journal of Lipid Research

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The distribution of plasma lipoprotein[a] (Lp[a])concentrations, a risk factor for cardiovascular disease, varies greatly among racial groups, with African Americans having values that are shifted toward higher levels than those of whites. The underlying cause of this heterogeneity is unknown, but a role for " trans -acting" factors has been hypothesized. This study used genetic linkage analysis to localize genetic factors influencing Lp[a] levels in African Americans that were absent in other populations; linkage results were analyzed separately in non-Hispanic whites, Hispanic whites, and African Americans. As expected, all three samples showed highly significant linkage at the approximate location of the lysophosphatidic acid locus. The distribution of Lp[a] levels has been found to vary greatly among populations (7-11). In general, the distributions in non-Hispanic white populations have been found to be shifted toward low Lp[a] levels, whereas the distributions in African American populations have been found to be more bell shaped and shifted toward higher and greater risk-associated levels, (7,8,11). The underlying cause of these differences is unknown. Recent studies have demonstrated that the inverse relationship between apo[a] size and the level of Lp[a] in plasma is maintained in the African American population; however, the relationship is more sigmoid in shape, rather than having a clear linear relationship (12). Others have hypothesized that " trans -acting" factor(s) must exist that either increase the rate of secretion of apo [a] or decrease Lp[a]'s catabolism in African Americans relative to non-Hispanic whites (13). This study used genetic linkage analysis to test the hypothesis that there is a gene influencing plasma Lp[a] levels in African Americans that is not acting in whites. This other gene would be segregating among family members in the admixed African American population and thus would be detectable by genetic linkage analysis.

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Section: Discussionmentioning

confidence: 99%

Lack of genetic linkage evidence for a trans-acting factor having a large effect on plasma lipoprotein[a] levels in African Americans

Barkley

Brown

Hanis

et al. 2003

Journal of Lipid Research

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“…Because intronic Alu repeats are known to be abundant Van Leuven et al 2001), we determined their precise location within the LDLR locus. The software "repeat masker" (http://ftp.genome.washington.edu) aligns any DNA sequence with consensus Alu repeat sequences or any other genomic repeated sequence.…”

Section: Bioinformaticsmentioning

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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“…The genotyping of the previously described genomic variants (A217V, A775P, D2080N, D2632E, G4379S) was carried out according to van Leuven et al, 2001.…”

Section: Analysis Of Genomic Variantsmentioning

confidence: 99%

The LDL receptor-related protein (LRP1/A2MR) and coronary atherosclerosis - novel genomic variants and functional consequences

Schulz¹,

Schagdarsurengin²,

Greiser³

et al. 2002

Hum. Mutat.

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The LDL receptor-related protein/alpha 2-macroglobulin receptor (LRP1/A2MR) is a multifunctional cell-surface glycoprotein that endocytoses several structurally and functionally distinct ligands. In clinical studies different genomic variants of the LRP1/A2MR and its role in the development of degenerative diseases like atherosclerosis or Alzheimer's disease were studied. We screened for novel genomic variants of LRP1/A2MR and investigated the importance of these variants in 214 coronary patients suffering from myocardial infarction as well as in 224 healthy controls. We detected a novel C>G polymorphism at position -25 in the functionally important promoter region of LRP1/A2MR. This polymorphism (c.1-25C>G) leads to the creation of a new GC-box, recognized by the constitutively expressed SP 1 transcription factor. Investigating the LRP1/A2MR gene expression with respect to this polymorphism, carriers of the mutant G-allele were found to have a higher mRNA expression level. A novel polymorphism in exon 22 (c.4012C>T), and two novel polymorphisms in intron 24 (IVS24+123C>A and IVS24+690G>A) associated with a previously described polymorphism in exon 61 (c.10249G>A), were related to the development of myocardial infarction. Two novel rare genetic variants of exon 88 (c.13933C>T) and intron 88 (IVS88+15G>A) were identified in four patients with severe coronary symptoms. However, the LRP1/A2MR gene expression was found to be independent of all identified novel genomic variants as well as other previously described changes (A217V, A775P, D2080N, D2632E, G4379S) except the promoter polymorphism.

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Sequencing of the coding exons of the LRP1 and LDLR genes on individual DNA samples reveals novel mutations in both genes

Cited by 18 publications

References 45 publications

Lack of genetic linkage evidence for a trans-acting factor having a large effect on plasma lipoprotein[a] levels in African Americans

Lack of genetic linkage evidence for a trans-acting factor having a large effect on plasma lipoprotein[a] levels in African Americans

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

The LDL receptor-related protein (LRP1/A2MR) and coronary atherosclerosis - novel genomic variants and functional consequences

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