Denaturing gradient-gel electrophoresis screening of familial defective apolipoprotein B-100 in a mixed Asian cohort: two cases of arginine3500 → tryptophan mutation associated with a unique haplotype

Choong, Meng Ling; Koay, Evelyn Siew Chuan; Khoo, K.L.; Khaw, M.C; Sethi, Sunil

doi:10.1093/clinchem/43.6.916

Cited by 27 publications

(7 citation statements)

References 37 publications

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“…The PCR and SSCP conditions used were previously described . In the same way, the region of the apo B gene coding for the putative receptor-binding domain was amplified by PCR using the primers described by Choong et al (1997), and subsequently analyzed by SSCP.…”

Section: Dna Amplification Sscp Analysis and Dna Sequencingmentioning

confidence: 99%

Mutation analysis in 36 unrelated Spanish subjects with familial hypercholesterolemia: Identification of 3 novel mutations in the LDL receptor gene

et al. 2000

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We used the single strand conformation polymorphism (SSCP) method to investigate 36 apparently unrelated Spanish patients with familial hypercholesterolemia (FH) for mutations in the promoter region and the 18 exons and their flanking intron sequences of the low density lipoprotein receptor (LDLR) gene. Nineteen aberrant SSCP patterns were found, and the underlying mutations were characterized by DNA sequencing. In addition, we tested all patients for the presence of mutations in the gene coding for apolipoprotein B (apo B). Five missense mutations (Q71E, S156L, E256K, N543H and T705I), four nonsense mutations (W(‐18)X, E10X, Q133X and C255X), six frameshift mutations (211delG, 518delG, 1045delC, 2085del19, 2207insT and 2393del9) and five splicing mutations (313+1G‐>C, 1061‐8T‐>C, 1845+1G‐>C, 2140+5G‐>A and 2390‐1G‐>C) were identified in the LDLR gene. In total, we detected 20 mutations, 3 of which, designated 1045delC, 1845+1G‐>C and 2207insT, have not been previously described. Seven patients were found to carry two different mutations in the same allele: W(‐18)X and E256K (one patient), Q71E and 313+1G‐>C (two patients), 1061‐8T‐>C and T705I (two patients), 518delG and 2140+5G‐>A (one patient) and N543H and 2393del9 (one patient). As we expected, there is a broad spectrum of mutations in the LDLR gene, given the genetic heterogeneity of the Spanish population. Hum Mutat 15:483–484, 2000. © 2000 Wiley‐Liss, Inc.

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Section: Dna Amplification Sscp Analysis and Dna Sequencingmentioning

confidence: 99%

Mutation analysis in 36 unrelated Spanish subjects with familial hypercholesterolemia: Identification of 3 novel mutations in the LDL receptor gene

et al. 2000

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“…On the other hand, the positively charged lysine residue found in the detected LDLR variant might be affecting the recycling of the receptor ( Tai et al, 2001 ). The p.(Arg3500Trp) APOB variant detected in this patient was previously identified in an Asian population and was causing an LOF of APOB , a phenotype similar to that produced by p.(Arg3500GLn) APOB variant ( Choong et al, 1997 ; Tai et al, 2001 ). The double LDLR/APOB heterozygotes with exaggerated hypercholesterolemia phenotype were still responsive to lipid-lowering treatments.…”

Section: Digenic Familial Hypercholesterolemia Mutationsmentioning

confidence: 54%

The Digenic Causality in Familial Hypercholesterolemia: Revising the Genotype–Phenotype Correlations of the Disease

2021

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Genetically inherited defects in lipoprotein metabolism affect more than 10 million individuals around the globe with preponderance in some parts where consanguinity played a major role in establishing founder mutations. Mutations in four genes have been so far linked to the dominant and recessive form of the disease. Those players encode major proteins implicated in cholesterol regulation, namely, the low-density lipoprotein receptor (LDLR) and its associate protein 1 (LDLRAP1), the proprotein convertase substilin/kexin type 9 (PCSK9), and the apolipoprotein B (APOB). Single mutations or compound mutations in one of these genes are enough to account for a spectrum of mild to severe phenotypes. However, recently several reports have identified digenic mutations in familial cases that do not necessarily reflect a much severe phenotype. Yet, data in the literature supporting this notion are still lacking. Herein, we review all the reported cases of digenic mutations focusing on the biological impact of gene dosage and the potential protective effects of single-nucleotide polymorphisms linked to hypolipidemia. We also highlight the difficulty of establishing phenotype–genotype correlations in digenic familial hypercholesterolemia cases due to the complexity and heterogeneity of the phenotypes and the still faulty in silico pathogenicity scoring system. We finally emphasize the importance of having a whole exome/genome sequencing approach for all familial cases of familial hyperlipidemia to better understand the genetic and clinical course of the disease.

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“…The first was of Scottish and the second of Asian ancestry. Two other R3500W probands, a Chinese and a Malay, had this second haplotype (40).…”

Section: Discussionmentioning

confidence: 97%

The apolipoprotein B R3531C mutation: characteristics of 24 subjects from 9 kindreds

Pullinger

Gaffney

Gutiérrez

et al. 1999

Journal of Lipid Research

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Familial ligand-defective apolipoprotein B (apoB) is a group of disorders caused by mutations in the apoB gene. In this report the R3531C mutation is characterized further using a monoclonal antibody MB19/dynamic laser light scattering technique to measure ratios of Cys 3531 to normal low density lipoprotein (LDL) particles. All six subjects studied showed a preferential accumulation of particles carrying the defective apoB allotype. We determined binding properties of LDL from R3531C heterozygotes by measurement of high-affinity binding to LDL receptors on fibroblasts and its ability promote growth of U937 cells. LDL from R3531C heterozygotes, compared to normal LDL, had 49.3% of the binding affinity and was 74% as effective in a U937 cell proliferation assay. To identify new probands, we screened 2570 subjects for the R3531C mutation. Nine probands were found with 15 affected relatives. Of the seven haplotypes we uncovered, two were novel, while five were identical to one initially reported as associated with Cys 3531 . Three silent mutations were detected also: T3540T, N3542N and T3552T. Analysis of lipid profiles of R3531C families showed, as with the R3500Q mutation, variable expression of the phenotype, modulated by environmental and other genetic factors. Both mutations tend to produce lower plasma levels of LDL in affected subjects than do defects of the LDL receptor (familial hypercholesterolemia, FH). This study shows that the Cys 3531 LDL particles are not only defective at binding to the LDL receptor, as determined by two separate methods, but that in all cases they accumulate preferentially compared to the normal allotype.-

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Denaturing gradient-gel electrophoresis screening of familial defective apolipoprotein B-100 in a mixed Asian cohort: two cases of arginine3500 → tryptophan mutation associated with a unique haplotype

Cited by 27 publications

References 37 publications

Mutation analysis in 36 unrelated Spanish subjects with familial hypercholesterolemia: Identification of 3 novel mutations in the LDL receptor gene

Mutation analysis in 36 unrelated Spanish subjects with familial hypercholesterolemia: Identification of 3 novel mutations in the LDL receptor gene

The Digenic Causality in Familial Hypercholesterolemia: Revising the Genotype–Phenotype Correlations of the Disease

The apolipoprotein B R3531C mutation: characteristics of 24 subjects from 9 kindreds

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