A novel ApoA-I truncation (ApoA-IMytilene) associated with decreased ApoA-I production

Anthanont, Pimjai; Polisecki, Eliana; Asztalos, Bela F.; Diffenderfer, Margaret R.; Barrett, P. Hugh R.; Millar, John S.; Billheimer, Jeffrey T.; Cuchel, Marina; Rader, Daniel J.; Schaefer, Ernst J.

doi:10.1016/j.atherosclerosis.2014.05.935

Cited by 12 publications

(10 citation statements)

References 43 publications

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“…A novel apoA-I truncation (apoA-I Mytilene) due to a heterozygous nonsense mutation (Gln216) has been reported to be associated with markedly decreased levels of HDL-C and decreased total cholesterol efflux associated with premature CHD and is consistent with the model that the C-terminal domain is responsible for the initiation of the lipid binding and cholesterol efflux (53). Partial deletion of the C-terminal domain as shown in Figure 6 inhibits the lipid binding and interaction with ABCA1 resulting in low HDL and decreased cholesterol efflux.…”

Section: Introductionsupporting

confidence: 60%

Lipid-free Apolipoprotein A-I Structure: Insights into HDL Formation and Atherosclerosis Development

Mei

Atkinson

2015

Archives of Medical Research

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Apolipoprotein A-I is the major protein in high-density lipoprotein (HDL) and plays an important role during the process of reverse cholesterol transport (RCT). Knowledge of the high-resolution structure of full-length apoA-I is vital for a molecular understanding of the function of HDL at the various steps of the RCT pathway. Due to the flexible nature of apoA-I and aggregation properties, the structure of full-length lipid-free apoA-I has evaded description for over three decades. Sequence analysis of apoA-I suggested that the amphipathic α-helix is the structural motif of exchangeable apolipoprotein, and NMR, X-ray and MD simulation studies have confirmed this. Different laboratories have used different methods to probe the secondary structure distribution and organization of both the lipid-free and lipid-bound apoA-I structure. Mutation analysis, synthetic peptide models, surface chemistry and crystal structures have converged on the lipid-free apoA-I domain structure and function: the N-terminal domain [1–184] forms a helix bundle while the C-terminal domain [185–243] mostly lacks defined structure and is responsible for initiating lipid-binding, aggregation and is also involved in cholesterol efflux. The first 43 residues of apoA-I are essential to stabilize the lipid-free structure. In addition, the crystal structure of C-terminally truncated apoA-I suggests a monomer-dimer conversation mechanism mediated through helix 5 reorganization and dimerization during the formation of HDL. Based on previous research, we have proposed a structural model for full-length monomeric apoA-I in solution and updated the HDL formation mechanism through three intermediate states. Mapping the known natural mutations on the full-length monomeric apoA-I model provides insight into atherosclerosis development through disruption of the N-terminal helix bundle or deletion of the C-terminal lipid-binding domain.

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Section: Introductionsupporting

confidence: 60%

Lipid-free Apolipoprotein A-I Structure: Insights into HDL Formation and Atherosclerosis Development

Mei

Atkinson

2015

Archives of Medical Research

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“…In 2014 we reported a 68-year-old male with premature CVD since age 54 years, corneal arcus, and an HDL-C 14 mg/dL, apoA-I 57 mg/dL, and lack of very large α-1 HDL (24). His TG and LDL-C levels were normal, but have been further optimized with statin therapy.…”

Section: Apolipoprotein A-i Variantsmentioning

confidence: 99%

Diagnosis and treatment of high density lipoprotein deficiency

Schaefer

Anthanont

Diffenderfer

et al. 2016

Progress in Cardiovascular Diseases

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Low serum high density lipoprotein cholesterol level (HDL-C) < 40 mg/dL in men and < 50 mg/dL in women are a significant independent risk factor for cardiovascular disease (CVD), and are often observed in patients with hypertriglyceridemia, obesity, insulin resistance, and diabetes. Patients with marked deficiency of HDL-C (< 20 mg/dL) in the absence of secondary causes are much less common (< 1% of the population). These patients may have homozygous, compound heterozygous, or heterozygous defects involving the apolipoprotein (APO)AI, ABCA1, or lecithin:cholesterol acyl transferase genes, associated with Apo A-I Deficiency, ApoA-I Variants, Tangier Disease, Familial Lecithin:Cholesteryl Ester Acyltransferase Deficiency, and Fish Eye Disease. There is marked variability in laboratory and clinical presentation, and DNA analysis is necessary for diagnosis. These patients can develop premature CVD, neuropathy, kidney failure, neuropathy, hepatosplenomegaly and anemia. Treatment should be directed at optimizing all non-HDL risk factors.

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“…The concentration of apoA-I in mg/dL within each HDL subpopulation was calculated, as described previously. 1,3,4,11,12 These results showed that the mean apoA-I concentrations in very large a-1, large a-2, medium a-3, small a-4, and very small preb-1 HDL particles in affected family members were 15.7%, 53.6%, 76.5%, 119.4%, and 92.5%, respectively, of values in controls. The reductions in the very large a-1 and large a-2 HDL particles were significant (P , .05) compared with controls.…”

Section: Laboratory Analysismentioning

confidence: 62%

“…3,4,11 The concentrations of lipids, lipoproteins, apolipoproteins, and HDL particle profiles in the family members and control subjects are shown in Table 1. Compared with controls, the proband and her affected sons had significant increases in serum TG levels that were 185% of control values (P , .05), and significant reductions in serum HDL-C and apoA-I concentrations that were 10% and 35% of control values, respectively (both P , .05).…”

Section: Laboratory Analysismentioning

confidence: 99%

“…2 Based on our review of the literature, 82 apoA-I mutations have been reported in human subjects. 1,3,4 Most apoA-I mutations are missense mutations resulting in a change in the amino acid sequence of the full-length protein. Approximately 40% of apoA-I missense mutations are associated with low HDL-C and apoA-I concentrations, whereas the remaining mutations are associated with either normal HDL-C with or without hereditary amyloidosis.…”

Section: Introductionmentioning

confidence: 99%

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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

Anthanont

Asztalos

Polisecki³

et al. 2015

Journal of Clinical Lipidology

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A novel ApoA-I truncation (ApoA-IMytilene) associated with decreased ApoA-I production

Cited by 12 publications

References 43 publications

Lipid-free Apolipoprotein A-I Structure: Insights into HDL Formation and Atherosclerosis Development

Lipid-free Apolipoprotein A-I Structure: Insights into HDL Formation and Atherosclerosis Development

Diagnosis and treatment of high density lipoprotein deficiency

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

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