Low density lipoprotein receptor (LDLR) gene mutations in Canadian subjects with familial hypercholesterolemia, but not of French descent

Wang, Jian; Huff, Erin; Janecka, Lenny; Hegele, Robert A.

doi:10.1002/humu.1205

Cited by 33 publications

(18 citation statements)

References 13 publications

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“…The mutations detected in our sample are summarized in Table 2. Three of the mutations (367T>A, 377T>A, and 917C>A) are described for the first time and the rest (858C>A and 1301C>T) have been previously found in other populations (Hobbs et al 1992;Webb et al 1996;Day et al 1997;Mavroidis et al 1997;Nauck et al 2001;Wang et al 2001). These nucleotide changes constitute four missense mutations (S102T, F105Y, S265R, and T413M) and one nonsense mutation (S285X).…”

Section: Resultsmentioning

confidence: 79%

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: Resultsmentioning

confidence: 79%

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

et al. 2004

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“…At the molecular level, FH is now commonly diagnosed using exon-by-exon screening methods, such as exon-byexon sequence analysis (EBESA) of LDLR from genomic DNA (gDNA) (3,4). However, this method finds mutations in only ‫ف‬ 50% of clinically diagnosed FH patents (3,4).…”

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confidence: 99%

“…However, this method finds mutations in only ‫ف‬ 50% of clinically diagnosed FH patents (3,4). Part of the diagnostic gap is attributable to the heterogeneity of AD FH (5).…”

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confidence: 99%

Multiplex ligation-dependent probe amplification of LDLR enhances molecular diagnosis of familial hypercholesterolemia

Wang

Ban

Hegele

2005

Journal of Lipid Research

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Autosomal dominant (AD) familial hypercholesterolemia [FH; Mendelian Inheritance in Man (MIM) 143890]typically results from mutations in the LDL receptor gene ( LDLR ), which are now commonly diagnosed using exon-byexon screening methods, such as exon-by-exon sequence analysis (EBESA) of genomic DNA (gDNA). However, many patients with FH have no LDLR mutation identified by this method. Part of the diagnostic gap is attributable to the genetic heterogeneity of AD FH, but another possible explanation is inadequate sensitivity of EBESA to detect certain mutation types, such as large deletions or insertions in LDLR . Affected individuals have increased plasma LDL cholesterol, which without adequate diagnosis and intervention can increase the risk of fatal coronary heart disease by up to 100-fold compared with the general population (2).Fortunately, treatment with statin drugs can substantially reduce this risk and improve clinical outcome (2), stressing the importance of early and accurate diagnosis.At the molecular level, FH is now commonly diagnosed using exon-by-exon screening methods, such as exon-byexon sequence analysis (EBESA) of LDLR from genomic DNA (gDNA) (3, 4). However, this method finds mutations in only ‫ف‬ 50% of clinically diagnosed FH patents (3, 4). Part of the diagnostic gap is attributable to the heterogeneity of AD FH (5). For instance, HCHOLAD2 (MIM 144010), which results from a missense mutation in APOB affecting the LDL receptor binding domain of apolipoprotein B-100 (apoB-100; MIM 107730) (6, 7), accounts for 5-10% of the AD FH phenotype. A rare FH subtype called HCHOLAD3 (MIM 603776) results from mutations in PCSK9 (MIM 607786), encoding neural apoptosis-regulated convertase-1 (5, 8, 9). A similarly rare autosomal recessive FH subtype called HCHOLAR1 (MIM 603813) results from mutations in ARH (MIM 605747), encoding a putative adaptor for the LDL receptor (10). However, even after accounting for genetic heterogeneity, many clinically diagnosed FH patients have no LDLR mutation with EBESA.Another possible explanation for the gap in FH molecular diagnosis is inadequate sensitivity of EBESA to detect certain mutation types, such as large deletions or insertions. The larger gDNA alterations create effective hemizygosity for single exons and result in an EBESA profile that is indistinguishable from homozygosity for two normal LDLR alleles. Multiplex ligation-dependent probe amplification (MLPA) is a new analytical method (11) that detects larger gDNA deletions or insertions that would otherwise be overlooked by EBESA (12). We hypothesized that some FH patients with no LDLR mutation detectable by EBESA would have an abnormality detectable using MLPA. Of 70 unrelated FH patients, 44 had LDLR mutations detected by EBESA, including missense, RNA splic-

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“…The resulting elevation of plasma LDL cholesterol concentrations is associated with development of cholesterol deposits in the cornea, called corneal arcus, on their eyelids and extensor tendons, called xanthelasmas and xanthomas, respectively, and in their vessel walls, leading to atherosclerosis and up to 100 times greater risk of coronary heart disease (CHD) for men under 45 years of age (Yuan et al, 2006;Pollex and Hegele, 2007). The molecular mechanism for disease in the majority of HeFH patients are small insertions or deletions, or missense, splicing, or nonsense mutations within the LDL receptor gene ( LDLR , MIM 606945), the majority of which were identified through sequencing of the coding exons and intron-exon boundaries using an approach called exon-byexon sequence analysis (EBESA) (Wang et al, 2001). Over 500 different missense mutations and over 200 small insertions and deletions have been reported within LDLR (Stenson et al, 2003).…”

Section: Rare Cnvs Causing Hefhmentioning

confidence: 99%

Copy number variation in metabolic phenotypes

Lanktree

Hegele

2008

Cytogenet Genome Res

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Despite successes in identifying genetic contributors to common metabolic phenotypes, only part of the heritable component of these traits has thus far been explained. Copy number variation (CNV) is likely to be responsible for some of the unexplained variation. As observed with single nucleotide changes, it is probable that both rare and common CNVs will contribute to susceptibility to metabolic disease. For instance, CNVs in the LDLR gene underlie a substantial portion of disease in patients with heterozygous familial hypercholesterolemia. As well, a common CNV in LPA encoding apolipoprotein(a) is the primary determinant of plasma lipoprotein(a) concentrations, a risk factor for atherosclerosis. Recent efforts to map CNVs in control populations have defined their size, frequency and distribution. Many of the identified CNVs overlap genes with important functions in metabolic pathways. The overlap of CNVs that were found in control datasets with functional candidate genes or genes with previous evidence of association with metabolic syndrome presents an important subset for future CNV association studies. Finally, we describe an approach to search for CNVs in a rare high-penetrance metabolic disorder, namely lipodystrophy. As methods to identify CNVs increase in precision and accuracy, the prospect of identifying their role in both rare Mendelian and common complex metabolic phenotypes will become a reality.

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Low density lipoprotein receptor (LDLR) gene mutations in Canadian subjects with familial hypercholesterolemia, but not of French descent

Cited by 33 publications

References 13 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

Multiplex ligation-dependent probe amplification of LDLR enhances molecular diagnosis of familial hypercholesterolemia

Copy number variation in metabolic phenotypes

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