Case report: A novel apolipoprotein A-I missense mutation apoA-I (Arg149Ser)Boston associated with decreased lecithin-cholesterol acyltransferase activation and cellular cholesterol efflux

Anthanont, Pimjai; Asztalos, Bela F.; Polisecki, Eliana; Zachariah, Benoy; Schaefer, Ernst J.

doi:10.1016/j.jacl.2015.02.005

Cited by 8 publications

(4 citation statements)

References 23 publications

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“…In addition to the HDL deficiency, her plasma had a decreased ability to esterify cholesterol. She and her kindred have been previously reported (35). An APOA1 in-frame deletion c.391_393delAAG (p.K131del) was found in four subjects, one of whom (APOA1-07), a man aged 71 years, had ASCVD.…”

Section: Apoa1 Mutations and Variantsmentioning

confidence: 96%

Genetic and secondary causes of severe HDL deficiency and cardiovascular disease

Geller

Polisecki²,

Diffenderfer³

et al. 2018

Journal of Lipid Research

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Supplementary key words apoA-I • ABCA1 • lecithin:cholesterol acyltransferase • lipoprotein lipase • high density lipoprotein metabolism • reverse cholesterol metabolism • dyslipidemia • genes in lipid disorders It has been concluded that genetic HDL deficiency is not causative for atherosclerotic cardiovascular disease (ASCVD), in contrast to genetic hypercholesterolemia associated with elevated levels of LDL cholesterol (LDL-C) or genetic hypertriglyceridemia (1, 2). This assessment has been reported in high-impact journals by a very large number of authors, representing some of the most prominent and well-known scientists in our field. The data generated stem from a very large number of subjects studied with and without ASCVD. The analyses, however, were based entirely on SNPs, mainly in intronic DNA regions, and excluded the four most important genes that regulate HDL cholesterol (HDL-C) levels: ABCA1, LCAT, APOA1, and LPL. The exclusions were justified by study findings that 1) genetic variations at the ABCA1, LCAT, APOA1, and LPL gene loci also affect TG and/or LDL-C levels and 2) an LIPC variant was not associated with ASCVD (1, 2). In our view this justification is flawed. Our recent review of severe HDL deficiency has documented that patients with HDL-C levels <20 mg/dl in the absence of secondary causes may have premature ASCVD, especially if such patients are homozygous or compound heterozygous for mutations in the APOA1 or ABCA1 genes (3).

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Section: Apoa1 Mutations and Variantsmentioning

confidence: 96%

Genetic and secondary causes of severe HDL deficiency and cardiovascular disease

Geller

Polisecki²,

Diffenderfer³

et al. 2018

Journal of Lipid Research

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“…Similarly, subjects carrying apoA-I Nichinan , an apoA-I variant with a deletion of residue E253 in the C-terminal helical region, presented HDL with a reduced ABCA1-mediated cholesterol efflux capacity, as a result of the impaired apoA-I Nichinan -ABCA1 direct interaction and lipid affinity [92]. An heterozygous apoA-I missense mutation, known as apoA-I Boston (c.517C.A, p.Arg149Ser), causing a reduction in HDL-C, free apoA-I levels and apoA-I content in very large HDL, leads to a reduction in total, ABCA1-and SR-BI-mediated CEC, probably as a consequence of the reduction in HDL mass [93]. Furthermore, three heterozygous missense mutations, Leu141Arg (apoA-I Pisa ) [94], Arg160Leu (apoA-I Oslo ) [95] and Pro165Arg [96], respectively, are associated with decreased LCAT activity, low HDL-C and decreased cholesterol efflux.…”

Section: Genic Alterations Leading To Hypoalphalipoproteinemiamentioning

confidence: 99%

High Density Lipoprotein Cholesterol Efflux Capacity and Atherosclerosis in Cardiovascular Disease: Pathophysiological Aspects and Pharmacological Perspectives

Adorni

Ronda

Bernini

et al. 2021

Cells

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Over the years, the relationship between high-density lipoprotein (HDL) and atherosclerosis, initially highlighted by the Framingham study, has been revealed to be extremely complex, due to the multiple HDL functions involved in atheroprotection. Among them, HDL cholesterol efflux capacity (CEC), the ability of HDL to promote cell cholesterol efflux from cells, has emerged as a better predictor of cardiovascular (CV) risk compared to merely plasma HDL-cholesterol (HDL-C) levels. HDL CEC is impaired in many genetic and pathological conditions associated to high CV risk such as dyslipidemia, chronic kidney disease, diabetes, inflammatory and autoimmune diseases, endocrine disorders, etc. The present review describes the current knowledge on HDL CEC modifications in these conditions, focusing on the most recent human studies and on genetic and pathophysiologic aspects. In addition, the most relevant strategies possibly modulating HDL CEC, including lifestyle modifications, as well as nutraceutical and pharmacological interventions, will be discussed. The objective of this review is to help understanding whether, from the current evidence, HDL CEC may be considered as a valid biomarker of CV risk and a potential pharmacological target for novel therapeutic approaches.

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“…33–34 For instance, post-translationally modified variants such as W72-oxidized ApoA-I and a truncated form at S228 were shown to poorly mediate HDL efflux in vitro . 35–36 Interestingly, in the case of W72-oxidized ApoA-I, higher concentration of this particular proteoform were associated with CVD events in a small clinical sample.…”

Section: Resultsmentioning

confidence: 99%

“…Notably, most data on modifications of ApoA-I suggest that noncanonical chemical variants are associated with lower efflux capacity or a null effect on efflux. , For instance, post-translationally modified variants such as W72-oxidized ApoA-I and a truncated form at S228 were shown to poorly mediate HDL efflux in vitro. , Interestingly, in the case of W72-oxidized ApoA-I, higher concentration of this particular proteoform were associated with CVD events in a small clinical sample. Our study, however, is the first to suggest that certain noncanonical, endogenous proteoforms of ApoA-I are associated with higher efflux values.…”

Section: Resultsmentioning

confidence: 99%

A Targeted, Differential Top-Down Proteomic Methodology for Comparison of ApoA-I Proteoforms in Individuals with High and Low HDL Efflux Capacity

Seckler¹,

Fornelli²,

Mutharasan

et al. 2018

J. Proteome Res.

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Top-down proteomics (TDP) allows precise determination/characterization of the different proteoforms derived from the expression of a single gene. In this study, we targeted apolipoprotein A-I (ApoA-I), a mediator of high-density-lipoprotein cholesterol efflux (HDL-E), which is inversely associated with coronary heart disease risk. Absolute ApoA-I concentration and allelic variation only partially explain inter-individual HDL-E variation. Therefore, we hypothesize that differences in HDL-E are associated with the abundances of different ApoA-I proteoforms. Here, we present a targeted TDP methodology to characterize ApoA-I proteoforms in serum samples and compare their abundances between individuals. We characterized eighteen ApoA-I proteoforms using selected-ion monitoring coupled to electron-transfer dissociation mass spectrometry. We then compared the abundances of these proteoforms between two groups of four participants, representing the individuals with highest and lowest HDL-E values within the Chicago Healthy Aging Study (n=420). Six proteoforms showed significantly (p<0.0005) higher intensity in high HDL-E individuals: canonical ApoA-I [fold difference (fd)=1.17], carboxymethylated ApoA-I (fd=1.24) and, with highest difference, four fatty acylated forms: palmitoylated (fd=2.16), oleoylated (fd=2.08), arachidonoylated (fd=2.31) and one bearing two modifications: palmitoylation and truncation (fd=2.13). These results demonstrate translational potential for targeted TDP in revealing, with high sensitivity, associations between inter-individual proteoform variation and physiological differences underlying disease risk.

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Case report: A novel apolipoprotein A-I missense mutation apoA-I (Arg149Ser)Boston associated with decreased lecithin-cholesterol acyltransferase activation and cellular cholesterol efflux

Cited by 8 publications

References 23 publications

Genetic and secondary causes of severe HDL deficiency and cardiovascular disease

Genetic and secondary causes of severe HDL deficiency and cardiovascular disease

High Density Lipoprotein Cholesterol Efflux Capacity and Atherosclerosis in Cardiovascular Disease: Pathophysiological Aspects and Pharmacological Perspectives

A Targeted, Differential Top-Down Proteomic Methodology for Comparison of ApoA-I Proteoforms in Individuals with High and Low HDL Efflux Capacity

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