ABCMdb

ABCA1 p.Pro1065Ser

Predicted by SNAP2:	A: D (63%), C: D (66%), D: D (75%), E: D (85%), F: D (85%), G: D (71%), H: D (80%), I: D (80%), K: D (85%), L: D (80%), M: D (80%), N: D (75%), Q: D (75%), R: D (85%), S: D (63%), T: D (66%), V: D (71%), W: D (91%), Y: D (85%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Genetic variation in the ABCA1 gene, HDL cholester... Atherosclerosis. 2010 Feb;208(2):305-16. Epub 2009 Jun 11. Frikke-Schmidt R
Genetic variation in the ABCA1 gene, HDL cholesterol, and risk of ischemic heart disease in the general population.
Atherosclerosis. 2010 Feb;208(2):305-16. Epub 2009 Jun 11., [PMID:19596329]

Abstract [show]
Epidemiological studies consistently demonstrate a strong inverse association between low levels of high-density lipoprotein (HDL) cholesterol and increased risk of ischemic heart disease (IHD). This review focuses on whether both rare and common genetic variation in ABCA1 contributes to plasma levels of HDL cholesterol and to risk of IHD in the general population, and further seeks to understand whether low levels of HDL cholesterol per se are causally related to IHD. Studies of the ABCA1 gene demonstrate a general strategy for detecting functional genetic variants, and show that both common and rare ABCA1 variants contribute to levels of HDL cholesterol and risk of IHD in the general population. The association between ABCA1 variants and risk of IHD appears, however, to be independent of plasma levels of HDL cholesterol. With the recent identification of the largest number of individuals heterozygous for loss-of-function mutations in ABCA1 worldwide, population studies suggests that genetically low HDL cholesterol per se does not predict an increased risk of IHD, and thus questions the causality of isolated low levels of HDL cholesterol for the development of IHD.

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2342 Genotyping revealed 28 het- erozygous carriers of P1065S, G1216V, N1800H, and R2144X in the CCHS (n = 9022), and 76 heterozygous carriers of G1216V, N1800H, and R2144 in the Copenhagen General Population Study (CGPS) (n = 31,241) [66]. Login to comment
2343 By large-scale genotyping, and confirmed by in vitro cellular cholesterol efflux assays, Frikke-Schmidt et al. showed that the P1065S, G1216V, and N1800H were indeed loss-of-function mutations causing low HDL cholesterol levels in the general population. Login to comment

[hide] ABCA1 gene mutations, HDL cholesterol levels, and ... JAMA. 2008 Nov 5;300(17):1997-8; author reply 1998. Brunham LR, Kastelein JJ, Hayden MR
ABCA1 gene mutations, HDL cholesterol levels, and risk of ischemic heart disease.
JAMA. 2008 Nov 5;300(17):1997-8; author reply 1998., [PMID:18984885]

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54 Third, our findings are consistent with our previous reports on the same cohort showing that polymorphisms and mutations in ABCA1 may or may not affect HDL levels, but that risk of IHD is independent of these HDL effects.2-4 Fourth, it is not correct that to state that heterozygosity for the 3 rare mutations in the CCHS (P1065S, G1216V, or R2144X; n=6) was associated with a 25% reduction in LDL cholesterol levels compared with noncarriers because this was not statistically significant. Login to comment
61 Third, our findings are consistent with our previous reports on the same cohort showing that polymorphisms and mutations in ABCA1 may or may not affect HDL levels, but that risk of IHD is independent of these HDL effects.2-4 Fourth, it is not correct that to state that heterozygosity for the 3 rare mutations in the CCHS (P1065S, G1216V, or R2144X; n=6) was associated with a 25% reduction in LDL cholesterol levels compared with noncarriers because this was not statistically significant. Login to comment

[hide] Association of loss-of-function mutations in the A... JAMA. 2008 Jun 4;299(21):2524-32. Frikke-Schmidt R, Nordestgaard BG, Stene MC, Sethi AA, Remaley AT, Schnohr P, Grande P, Tybjaerg-Hansen A
Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease.
JAMA. 2008 Jun 4;299(21):2524-32., [PMID:18523221]

Abstract [show]
CONTEXT: Low levels of high-density lipoprotein (HDL) cholesterol are inversely related to cardiovascular risk. Whether this is a causal effect is unclear. OBJECTIVE: To determine whether genetically reduced HDL cholesterol due to heterozygosity for 4 loss-of-function mutations in ABCA1 cause increased risk of ischemic heart disease (IHD). DESIGN, SETTING, AND PARTICIPANTS: Three studies of white individuals from Copenhagen, Denmark, were used: the Copenhagen City Heart Study (CCHS), a 31-year prospective general population study (n = 9022; 28 heterozygotes); the Copenhagen General Population Study (CGPS), a cross-sectional general population study (n = 31,241; 76 heterozygotes); and the Copenhagen Ischemic Heart Disease Study (CIHDS), a case-control study (n = 16,623; 44 heterozygotes). End points in all 3 studies were recorded during the period of January 1, 1976, through July 9, 2007. MAIN OUTCOME MEASURES: Levels of HDL cholesterol in the general population, cellular cholesterol efflux, and the association between IHD and HDL cholesterol and genotype. RESULTS: Heterozygotes vs noncarriers for 4 ABCA1 mutations (P1065S, G1216V, N1800H, R2144X) had HDL cholesterol levels of 41 mg/dL (interquartile range, 31-50 mg/dL) vs 58 mg/dL (interquartile range, 46-73 mg/dL), corresponding to a reduction in HDL cholesterol of 17 mg/dL (P < .001). A 17-mg/dL lower HDL cholesterol level in the CCHS was associated with a multifactorially adjusted hazard ratio for IHD of 1.70 (95% confidence interval [CI], 1.57-1.85). However, for IHD in heterozygotes vs noncarriers, the multifactorially adjusted hazard ratio was 0.67 (95% CI, 0.28-1.61; 1741 IHD events) in the CCHS, the multifactorially adjusted odds ratio was 0.82 (95% CI, 0.34-1.96; 2427 IHD events) in the CGPS, and the multifactorially adjusted odds ratio was 0.86 (95% CI, 0.32-2.32; 2498 IHD cases) in the CIHDS. The corresponding odds ratio for IHD in heterozygotes vs noncarriers for the combined studies (n = 41,961; 6666 cases; 109 heterozygotes) was 0.93 (95% CI, 0.53-1.62). CONCLUSION: Lower plasma levels of HDL cholesterol due to heterozygosity for loss-of-function mutations in ABCA1 were not associated with an increased risk of IHD.

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12 Results Heterozygotes vs noncarriers for 4 ABCA1 mutations (P1065S, G1216V, N1800H, R2144X) had HDL cholesterol levels of 41 mg/dL (interquartile range, 31-50 mg/dL) vs 58 mg/dL (interquartile range, 46-73 mg/dL), corresponding to a reduction in HDL cholesterol of 17 mg/dL (PϽ.001). Login to comment
26 The 9022 individuals were genotyped for all non-synonymous mutations (S364C, T774P, K776N, P1065S, G1216V, N1800H, R2144X [http://www.hgmd.cf.ac.uk/ac /index.php; http://www.mutdb.org]), which were previously identified by resequencing the promoter, coding region,andconsensussplicesitesofABCA1 in 190 individuals of Danish ancestry with high and low HDL cholesterol levels.13 All end points and data collection were recorded in the follow-up period of January 1, 1976, through July 9, 2007. Login to comment
39 Participants in the CIHDS were genotyped for the 4 mutations (P1065S, G1216V, N1800H, R2144X) associated with reduced HDL cholesterol levels in the CCHS and the CGPS. Login to comment
48 HeLa cells were transfected (ExGen 500 in vitro transfection reagent, Fermentas Inc, Hanover, Maryland) with plasmids expressing the ABCA1 mutations (P1065S, G1216V, N1800H) created by site-directed mutagenesis (Quick- Change II XL Site-Directed Mutagenesis Kit, Stratagene Inc, La Jolla, California);R2144Xhaspreviouslybeenshown to cause reduced cholesterol efflux.7 Sequences of all plasmids were confirmed by direct sequencing (Applied Biosys- temsInc),andtransfectionefficiencywas examined by flow cytometry of transfected HeLa cells. Login to comment
60 On a continuous scale, a 17-mg/dL (to convert to mmol/L, multiply by 0.0259) lower HDL cholesterol level associated with a multifactorially adjusted HR for IHD of 1.70 (95% CI, 1.57-1.85), similar to that reported in other studies.1 ABCA1 Mutation Heterozygotes and Plasma HDL Cholesterol Four of 7 mutations (P1065S, G1216V, N1800H, R2144X) were associated with Figure 1. Login to comment
69 Number of Participants Heterozygous for Missense or Nonsense Mutations in ABCA1 in the Studied Populations Mutation CCHS (n = 9022) CGPS (n = 31 241) CIHDS (n = 2498) P1065S 1 0 0 G1216V 3 3 1 N1800H 22 70 3 R2144X 2 3 1 Abbreviations: CCHS, Copenhagen City Heart Study; CGPS, Copenhagen General Population Study; CIHDS, Copenhagen Ischemic Heart Disease Study. Login to comment
72 The overall heterozygote frequency in the general population was approximately 3:1000 in both the CCHS and the CGPS, the majority carrying the N1800H mutation. Login to comment
78 ABCA1 Mutations and Cellular Cholesterol Efflux in Vitro In agreement with the observed lower plasma HDL cholesterol levels associated with these mutations in vivo, 4 mutations were associated with impaired cholesterol efflux in vitro: 79% (95% CI, 56%-103%) for P1065S, 74% (95% CI, 54%-95%) for G1216V, 49% (95% CI, 37%-60%) for N1800H, and 48%7 for R2144X compared with 100% in wild-type (P=.04 for all). Login to comment
88 bProbands heterozygous for P1065S, G1216V, or R2144X. Login to comment
89 cProbands heterozygous for P1065S, G1216V, R2144X, or N1800H. Login to comment
100 When restricting the analyses to N1800H heterozygotes (n=95), the equivalent OR was 0.77 (95% CI, 0.41-1.45); with 80% statistical power to exclude an OR of 1.85 or more. Login to comment
111 Plasma High-Density Lipoprotein (HDL) Cholesterol and Apolipoprotein A-I Levels for Heterozygous Carriers of ABCA1 Mutations in the Copenhagen City Heart Study 120 80 60 100 40 20 0 20 40 60 80 100 Women 120 80 60 100 40 20 0 20 40 60 80 100 Men HDL cholesterol 220 140 160 120 180 200 100 80 60 0 20 40 60 80 100 Women Age, y Age, y Age, y 200 160 140 180 120 100 80 60 0 20 40 60 80 100 Men Age, y Apolipoprotein A-I Mutation P1065S G1216V N1800H R2144X 95th 50th 5th 95th 50th 5th 95th 50th 5th 95th 50th 5th mg/dLmg/dL Exact values for each heterozygous mutation carrier are superimposed on the 5th, 50th, and 95th percentiles for age and sex as a whole (N=9022). Login to comment
119 P1065S was not identified in the Copenhagen General Population Study. Login to comment
25 The 9022 individuals were genotyped for all nonsynonymous mutations (S364C, T774P, K776N, P1065S, G1216V, N1800H, R2144X [http://www.hgmd.cf.ac.uk/ac /index.php; http://www.mutdb.org]), which were previously identified by resequencing the promoter, coding region,andconsensussplicesitesofABCA1 in 190 individuals of Danish ancestry with high and low HDL cholesterol levels.13 All end points and data collection were recorded in the follow-up period of January 1, 1976, through July 9, 2007. Login to comment
38 Participants in the CIHDS were genotyped for the 4 mutations (P1065S, G1216V, N1800H, R2144X) associated with reduced HDL cholesterol levels in the CCHS and the CGPS. Login to comment
52 Plasma High-Density Lipoprotein (HDL) Cholesterol and Apolipoprotein A-I Levels for Heterozygous Carriers of ABCA1 Mutations in the Copenhagen City Heart Study 120 80 60 100 40 20 0 20 40 60 80 100 Women 120 80 60 100 40 20 0 20 40 60 80 100 Men HDL cholesterol 220 140 160 120 180 200 100 80 60 0 20 40 60 80 100 Women Age, y Age, y Age, y 200 160 140 180 120 100 80 60 0 20 40 60 80 100 Men Age, y Apolipoprotein A-I Mutation P1065S G1216V N1800H R2144X 95th 50th 5th 95th 50th 5th 95th 50th 5th 95th 50th 5th mg/dL mg/dL Exact values for each heterozygous mutation carrier are superimposed on the 5th, 50th, and 95th percentiles for age and sex as a whole (N=9022). Login to comment
62 ABCA1 Mutations and Cellular Cholesterol Efflux in Vitro In agreement with the observed lower plasma HDL cholesterol levels associated with these mutations in vivo, 4 mutations were associated with impaired cholesterol efflux in vitro: 79% (95% CI, 56%-103%) for P1065S, 74% (95% CI, 54%-95%) for G1216V, 49% (95% CI, 37%-60%) for N1800H, and 48%7 for R2144X compared with 100% in wild-type (P=.04 for all). Login to comment
73 cProbands heterozygous for P1065S, G1216V, R2144X, or N1800H. Login to comment

[hide] Variations on a gene: rare and common variants in ... Annu Rev Nutr. 2006;26:105-29. Brunham LR, Singaraja RR, Hayden MR
Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis.
Annu Rev Nutr. 2006;26:105-29., [PMID:16704350]

Abstract [show]
Cholesterol and its metabolites play a variety of essential roles in living systems. Virtually all animal cells require cholesterol, which they acquire through synthesis or uptake, but only the liver can degrade cholesterol. The ABCA1 gene product regulates the rate-controlling step in the removal of cellular cholesterol: the efflux of cellular cholesterol and phospholipids to an apolipoprotein acceptor. Mutations in ABCA1, as seen in Tangier disease, result in accumulation of cellular cholesterol, reduced plasma high-density lipoprotein cholesterol, and increased risk for coronary artery disease. To date, more than 100 coding variants have been identified in ABCA1, and these variants result in a broad spectrum of biochemical and clinical phenotypes. Here we review genetic variation in ABCA1 and its critical role in cholesterol metabolism and atherosclerosis in the general population.

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555 Since a complete loss of function allele would be expected to result in a 50% reduction in HDL levels, a greater than 50% reduction in HDL is most likely explained by a dominant negative allele, in which TABLE 3 Patient phenotypes associated with heterozygous ABCA1 mutations Mutation HDL (mmol/L) HDL (% of control) Number of patients M1091T 0.48 ± 0.5 30 ± 30 4 G1216V 0.50 40 1 R2144X 0.56 ± 0.2 41 ± 18 12 R282X 0.52 41 1 R909X 0.59 ± 0.3 42 ± 19 5 K776N 0.55 ± 0.1 47 ± 5 2 R587W 0.61 ± 0.1 47 ± 8 7 S364C 0.60 48 1 P1065S 0.80 51 1 c-ter deletion 0.75 53 1 N1800H - 56.5 33 P85L 0.72 ± 0.4 57 ± 33 5 Del693L 0.79 ± 0.2 57 ± 15 8 D1289N 0.80 ± 0.1 59 ± 12 4 R2081W 0.80 ± 0.1 59 ± 12 4 2203X 0.80 ± 0.2 59 ± 20 4 DelED1893,4 0.77 ± 0.2 59 ± 18 8 2145X 0.82 ± 0.1 59 ± 9 4 A1046D 0.70 ± 0.1 60 ± 8 2 Q597R 0.82 ± 0.1 60 ± 5 5 C1477R 0.82 ± 0.2 61 ± 15 9 IVS25 + 1G > C 0.78 ± 0.1 62 ± 12 4 D1099Y 0.83 ± 0.3 63 ± 21 5 1552X 1.00 64 1 F2009S 0.82 ± 0.2 64 ± 19 6 R587W 0.86 ± 0.1 65 ± 17 2 R1068H 0.90 ± 0.3 67 ± 26 9 N935S 1.00 ± 0.3 74 ± 16 7 T929I 1.01 ± 0.2 76 ± 7 8 1284X 1.11 ± 0.2 83 ± 14 5 A937V 1.15 ± 0.6 85 ± 28 2 R1680W 1.22 ± 0.2 87 ± 17 3 635X 1.24 ± 0.5 90 ± 32 7 W590S 1.32 ± 0.6 103 ± 46 15 the mutant protein actually interferes with the activity of the remaining wild-type protein. Login to comment

[hide] ATP-binding cassette transporters, atherosclerosis... Circ Res. 2014 Jan 3;114(1):157-70. doi: 10.1161/CIRCRESAHA.114.300738. Westerterp M, Bochem AE, Yvan-Charvet L, Murphy AJ, Wang N, Tall AR
ATP-binding cassette transporters, atherosclerosis, and inflammation.
Circ Res. 2014 Jan 3;114(1):157-70. doi: 10.1161/CIRCRESAHA.114.300738., [PMID:24385509]

Abstract [show]
Although recent genome-wide association studies have called into question the causal relationship between high-density lipoprotein (HDL) cholesterol levels and cardiovascular disease, ongoing research in animals and cells has produced increasing evidence that cholesterol efflux pathways mediated by ATP-binding cassette (ABC) transporters and HDL suppress atherosclerosis. These differing perspectives may be reconciled by a modified HDL theory that emphasizes the antiatherogenic role of cholesterol flux pathways, initiated in cells by ABC transporters. ABCA1 and ABCG1 control the proliferation of hematopoietic stem and multipotential progenitor cells in the bone marrow and hematopoietic stem and multipotential progenitor cell mobilization and extramedullary hematopoiesis in the spleen. Thus, activation of cholesterol efflux pathways by HDL infusions or liver X receptor activation results in suppression of hematopoietic stem and multipotential progenitor cell mobilization and extramedullary hematopoiesis, leading to decreased production of monocytes and neutrophils and suppression of atherosclerosis. In addition, macrophage-specific knockout of transporters has confirmed their role in suppression of inflammatory responses in the arterial wall. Recent studies have also shown that ABCG4, a close relative of ABCG1, controls platelet production, atherosclerosis, and thrombosis. ABCG4 is highly expressed in megakaryocyte progenitors, where it promotes cholesterol efflux to HDL and controls the proliferative responses to thrombopoietin. Reconstituted HDL infusions act in an ABCG4-dependent fashion to limit hypercholesterolemia-driven excessive platelet production, thrombosis, and atherogenesis, as occurs in human myeloproliferative syndromes. Activation of ABC transporter-dependent cholesterol efflux pathways in macrophages, hematopoietic stem and multipotential progenitor cells, or platelet progenitors by reconstituted HDL infusion or liver X receptor activation remain promising approaches to the treatment of human atherothrombotic diseases.

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59 In a Mendelian randomization approach in a prospective cohort comprising ࣈ9000 individuals, heterozygosity for the ABCA1 mutation K776N led to a 2-to-3 times higher risk of ischemic heart disease.105 Furthermore, 5 single-nucleotide polymorphisms (SNPs) inABCA1 (V771M,V825I, I883M, E1172D, R1587K) were shown to predict risk of ischemic heart disease in a cohort of 9259 individuals.106 However, the same group reported more recently that heterozygosity for 4 loss-of-function mutations (P1065S, G1216V, N1800H, R2144X) was not associated with a higher risk of ischemic heart disease in 3 prospective cohorts comprising 56ߙ886 individuals.107 It must be noted, however, that only small decreases in HDL, of ࣈ28% as opposed to ࣈ50% in previously reported ABCA1 heterozygotes, were observed.94,101-103,107 Also, the residual cholesterol efflux was substantial (74%-79% for P1065S and G1216V and 48%-49% for N1800H and R2144X for homozygous mutations compared with controls),107 whereas in patients with TD there was only 20% to 30% residual cholesterol efflux.108 In addition, LDL levels were reduced by ࣈ25%, probably offsetting the effects of reduced HDL on CVD.107 Thus, the conflicting results in these studies could be related to inclusion of relatively mild ABCA1 mutations as well as offsetting effects of reduced LDL cholesterol levels.109 In a meta-analysis of genome-wide association studies, SNPs near the ABCA1 gene have been associated with HDL and total cholesterol levels,110,111 but not with cardiovascular risk.112 Although these studies have the benefit of huge statistical power, some caution is merited in the interpretation of findings. Login to comment

[hide] ATP-binding cassette transporter A1: from metaboli... Neurobiol Dis. 2014 Dec;72 Pt A:13-21. doi: 10.1016/j.nbd.2014.05.007. Epub 2014 May 17. Koldamova R, Fitz NF, Lefterov I
ATP-binding cassette transporter A1: from metabolism to neurodegeneration.
Neurobiol Dis. 2014 Dec;72 Pt A:13-21. doi: 10.1016/j.nbd.2014.05.007. Epub 2014 May 17., [PMID:24844148]

Abstract [show]
ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux to lipid-free apolipoprotein A-I (apoA-I) and apolipoprotein E (apoE). ABCA1 is an essential regulator of high density lipoproteins (HDL) and reverse cholesterol transport - a role that determines its importance for atherosclerosis. Over the last 10 years studies have provided convincing evidence that ABCA1, via its control of apoE lipidation, also has a role in Alzheimer's disease (AD). A series of reports have revealed a significant impact of ABCA1 on Abeta deposition and clearance in AD model mice, as well as an association of common and rare ABCA1 gene variants with the risk for AD. Since APOE is the major genetic risk factor for late onset AD, the regulation of apoE level or its functionality by ABCA1 may prove significant for AD pathogenesis. ABCA1 is transcriptionally regulated by Liver X Receptors (LXR) and Retinoic X Receptors (RXR) which provides a starting point for drug discovery and development of synthetic LXR and RXR agonists for treatment of metabolic and neurodegenerative disorders. This review summarizes the recent results of research on ABCA1, particularly relevant to atherosclerosis and AD.

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932 For example, some of the ABCA1 missense mutations (P1065S, G1216V, N1800H, R2144X) cause only a mild decrease of cholesterol efflux which in heterozygous state results in a relatively small reduction of HDL (less than 30% decrease compared to the normal values) explaining the lack of atherosclerosis (Frikke-Schmidt et al., 2008). Login to comment

[hide] Subfraction analysis of circulating lipoproteins i... Clin Chim Acta. 2016 Jan 15;452:167-72. doi: 10.1016/j.cca.2015.11.021. Epub 2015 Nov 23. Murano T, Yamaguchi T, Tatsuno I, Suzuki M, Noike H, Takanami T, Yoshida T, Suzuki M, Hashimoto R, Maeno T, Terai K, Tokuyama W, Hiruta N, Schneider WJ, Bujo H
Subfraction analysis of circulating lipoproteins in a patient with Tangier disease due to a novel ABCA1 mutation.
Clin Chim Acta. 2016 Jan 15;452:167-72. doi: 10.1016/j.cca.2015.11.021. Epub 2015 Nov 23., [PMID:26616730]

Abstract [show]
Tangier disease, characterized by low or absent high-density lipoprotein (HDL), is a rare hereditary lipid storage disorder associated with frequent, but not obligatory, severe premature atherosclerosis due to disturbed reverse cholesterol transport from tissues. The reasons for the heterogeneity in atherogenicity in certain dyslipidemias have not been fully elucidated. Here, using high-performance liquid chromatography with a gel filtration column (HPLC-GFC), we have studied the lipoprotein profile of a 17-year old male patient with Tangier disease who to date has not developed manifest coronary atherosclerosis. The patient was shown to be homozygous for a novel mutation (Leu1097Pro) in the central cytoplasmic region of ATP-binding cassette transporter A1 (ABCA1). Serum total and HDL-cholesterol levels were 59mg/dl and 2mg/dl, respectively. Lipoprotein electrophoretic analyses on agarose and polyacrylamide gels showed the presence of massively abnormal lipoproteins. Further analysis by HPLC-GFC identified significant amounts of lipoproteins in low-density lipoprotein (LDL) subfractions. The lipoprotein particles found in the peak subfraction were smaller than normal LDL, were rich in triglycerides, but poor in cholesterol and phospholipids. These findings in an adolescent Tangier patient suggest that patients in whom these triglyceride-rich, cholesterol- and phospholipid-poor LDL-type particles accumulate over time, would experience an increased propensity for developing atherosclerosis.

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124 The mutations, Pro1065Ser and Met1091Thr, have been shown to disturb the ATP-binding function; these mutations cause FHA [7,19,21, 26]. Login to comment