ABCMdb

ABCA1 p.Trp1699Cys

Predicted by SNAP2:	A: D (85%), C: D (80%), D: D (95%), E: D (95%), F: D (80%), G: D (95%), H: D (95%), I: D (91%), K: D (95%), L: D (91%), M: D (85%), N: D (95%), P: D (95%), Q: D (91%), R: D (95%), S: D (91%), T: D (91%), V: D (91%), Y: D (80%),
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, P: D, Q: D, R: D, S: D, T: D, V: D, Y: D,

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[hide] Severe HDL deficiency due to novel defects in the ... J Intern Med. 2009 Mar;265(3):359-72. Epub 2008 Oct 25. Pisciotta L, Bocchi L, Candini C, Sallo R, Zanotti I, Fasano T, Chakrapani A, Bates T, Bonardi R, Cantafora A, Ball S, Watts G, Bernini F, Calandra S, Bertolini S
Severe HDL deficiency due to novel defects in the ABCA1 transporter.
J Intern Med. 2009 Mar;265(3):359-72. Epub 2008 Oct 25., [PMID:19019193]

Abstract [show]
OBJECTIVES: The objective was the identification and functional characterization of mutations in the ABCA1 gene in four patients with severe HDL deficiency. SUBJECTS: Patients were referred to the clinic because of almost complete HDL deficiency. METHODS: The ABCA1 gene was sequenced directly. The analysis of the ABCA1 protein, ABCA1 mRNA and ABCA1-mediated cholesterol efflux was performed in cultured fibroblasts. Intracellular localization of ABCA1 mutants was investigated in transfected HEK293 cells. RESULTS: Two patients were homozygous for mutations in the coding region of the ABCA1 gene, resulting in an amino acid substitution (p.A1046D) and a truncated protein (p.I74YFsX76). The third patient was homozygous for a splice site mutation in intron 35 (c.4773 + 1g>a), resulting in an in-frame deletion of 25 amino acids (del p.D1567_K1591) in ABCA1. These patients had clinical manifestations of accumulation of cholesterol in the reticulo-endothelial system. The fourth patient, with preclinical atherosclerosis, was a compound heterozygote for two missense mutations (p.R587W/p.W1699C). ABCA1-mediated cholesterol efflux was abolished in fibroblasts from patients with p.A1046D and del p.D1567_K1591 mutants and in fibroblasts homozygous for p.R587W. A reduced ABCA1 protein content was observed in these cells, suggesting an increased intracellular degradation. The mutant p.W1699C was largely retained in the endoplasmic reticulum, when expressed in HEK293 cells. CONCLUSIONS: The homozygotes for mutations which abolish ABCA1 function showed overt signs of involvement of the reticulo-endothelial system. This was not the case in the compound heterozygote for missense mutations, suggesting that this patient retains some residual ABCA1 function that reduces cholesterol accumulation in the reticulo-endothelial system.

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No. Sentence Comment
16 The fourth patient, with preclinical atherosclerosis, was a compound heterozygote for two missense mutations (p.R587W/p.W1699C). Login to comment
19 The mutant p.W1699C was largely retained in the endoplasmic reticulum, when expressed in HEK293 cells. Login to comment
75 Mutant ABCA1-GFP cDNA (corresponding to the naturally occurring mutant p.W1699C) was obtained by site-directed mutagenesis (Stratagene, La Jolla, CA, USA). Login to comment
98 p.D1567_K1591); M3 (p.I74YFsX76); M4 (p.W1699C); M5 (p.R587W); ND, not determined. Login to comment
147 The proband was found to be a compound heterozygote for the following mutations of the ABCA1 gene: (i) a C>T transition in exon 14 (c.1759 C>T, p.R587W), inherited from the mother; (ii) a G>T transversion in exon 37 (c.5097 G>T, p.W1699C), inherited from the father (Fig. S3). Login to comment
149 The sister (subject II.2) and the niece (subject III.1) of the proband were heterozygous for the p.W1699C mutation. Login to comment
187 Finally the mutant ABCA1-GFP p.W1699C (found in the compound heterozygote of family 4) was largely retained in the cytoplasm (Fig. 6c), mainly in the endoplasmic reticulum as demonstrated by the co-localization with calnexin (Fig. 6c, right panel). Login to comment
203 HEK293 cells were transiently transfected with pcDNA3.1 ABCA1-GFP wild type (a) ABCA1-GFP del p.K422_K1524 (an artificial mutant containing a large deletion spanning from exon 11 to exon 33) (b) and ABCA1-GFP p.W1699C (c) mutant vectors. Login to comment
215 The proband of family 4 was a compound heterozygote carrying two missense mutations (p.R587W and p.W1699C). Login to comment
223 The second missense mutation (p.W1699C) found in the proband of family 4 is a novel mutation, expected to have a deleterious effect on ABCA1 function, as indicated by computational analysis with PolyPhen, PANTHER and SIFT algorithms (Table S2). Login to comment
227 As an alternative, we expressed the p.W1699C mutant (ABCA1-GFP-W1699C) in HEK293 cells and examined its intracellular localization (Fig. 6c). Login to comment
229 It is possible that the p.W1699C mutant retains some residual function, as the plasma HDL-C levels found in the three family members carrying this mutation were not as low as might be expected in carriers of null ABCA1 alleles. Login to comment

[hide] Update on the molecular biology of dyslipidemias. Clin Chim Acta. 2015 Nov 4. pii: S0009-8981(15)30036-X. doi: 10.1016/j.cca.2015.10.033. Ramasamy I
Update on the molecular biology of dyslipidemias.
Clin Chim Acta. 2015 Nov 4. pii: S0009-8981(15)30036-X. doi: 10.1016/j.cca.2015.10.033., [PMID:26546829]

Abstract [show]
Dyslipidemia is a commonly encountered clinical condition and is an important determinant of cardiovascular disease. Although secondary factors play a role in clinical expression, dyslipidemias have a strong genetic component. Familial hypercholesterolemia is usually due to loss-of-function mutations in LDLR, the gene coding for low density lipoprotein receptor and genes encoding for proteins that interact with the receptor: APOB, PCSK9 and LDLRAP1. Monogenic hypertriglyceridemia is the result of mutations in genes that regulate the metabolism of triglyceride rich lipoproteins (eg LPL, APOC2, APOA5, LMF1, GPIHBP1). Conversely familial hypobetalipoproteinemia is caused by inactivation of the PCSK9 gene which increases the number of LDL receptors and decreases plasma cholesterol. Mutations in the genes APOB, and ANGPTL3 and ANGPTL4 (that encode angiopoietin-like proteins which inhibit lipoprotein lipase activity) can further cause low levels of apoB containing lipoproteins. Abetalipoproteinemia and chylomicron retention disease are due to mutations in the microsomal transfer protein and Sar1b-GTPase genes, which affect the secretion of apoB containing lipoproteins. Dysbetalipoproteinemia stems from dysfunctional apoE and is characterized by the accumulation of remnants of chylomicrons and very low density lipoproteins. ApoE deficiency can cause a similar phenotype or rarely mutations in apoE can be associated with lipoprotein glomerulopathy. Low HDL can result from mutations in a number of genes regulating HDL production or catabolism; apoAI, lecithin: cholesterol acyltransferase and the ATP-binding cassette transporter ABCA1. Patients with cholesteryl ester transfer protein deficiency have markedly increased HDL cholesterol. Both common and rare genetic variants contribute to susceptibility to dyslipidemias. In contrast to rare familial syndromes, in most patients, dyslipidemias have a complex genetic etiology consisting of multiple genetic variants as established by genome wide association studies. Secondary factors, obesity, metabolic syndrome, diabetes, renal disease, estrogen and antipsychotics can increase the likelihood of clinical presentation of an individual with predisposed genetic susceptibility to hyperlipoproteinemia. The genetic profiles studied are far from complete and there is room for further characterization of genes influencing lipid levels. Genetic assessment can help identify patients at risk for developing dyslipidemias and for treatment decisions based on 'risk allele' profiles. This review will present the current information on the genetics and pathophysiology of disorders that cause dyslipidemias.

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No. Sentence Comment
1064 All three mutations p.A1046D, p. Y1532C and p. W1699C were reported to be deleterious in functional studies (473). Login to comment