ABCG5 p.Asp450His
| Predicted by SNAP2: | A: N (72%), C: N (61%), E: N (78%), F: N (61%), G: N (66%), H: N (61%), I: D (53%), K: N (53%), L: N (61%), M: D (53%), N: N (82%), P: D (63%), Q: N (66%), R: N (57%), S: N (82%), T: N (72%), V: D (53%), W: D (75%), Y: N (72%), |
| Predicted by PROVEAN: | A: N, C: D, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N, |
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[hide] Systematic haplotype analysis resolves a complex p... Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13886-91. Epub 2009 Aug 10. Kenny EE, Gusev A, Riegel K, Lutjohann D, Lowe JK, Salit J, Maller JB, Stoffel M, Daly MJ, Altshuler DM, Friedman JM, Breslow JL, Pe'er I, Sehayek E
Systematic haplotype analysis resolves a complex plasma plant sterol locus on the Micronesian Island of Kosrae.
Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13886-91. Epub 2009 Aug 10., 2009-08-18 [PMID:19667188]
Abstract [show]
Pinpointing culprit causal variants along signal peaks of genome-wide association studies (GWAS) is challenging. To overcome confounding effects of multiple independent variants at such a locus and narrow the interval for causal allele capture, we developed an approach that maps local shared haplotypes harboring a putative causal variant. We demonstrate our method in an extreme isolate founder population, the pacific Island of Kosrae. We analyzed plasma plant sterol (PPS) levels, a surrogate measure of cholesterol absorption from the intestine, where previous studies have implicated 2p21 mutations in the ATP binding cassette subfamily G members 5 or 8 (ABCG5 or ABCG8) genes. We have previously reported that 11.1% of the islanders are carriers of a frameshift ABCG8 mutation increasing PPS levels in carriers by 50%. GWAS adjusted for this mutation revealed genomewide significant signals along 11 Mb around it. To fine-map this signal, we detected pairwise identity-by-descent haplotypes using our tool GERMLINE and implemented a clustering algorithm to identify haplotypes shared across multiple samples with their unique shared boundaries. A single 526-kb haplotype mapped strongly to PPS levels, dramatically refining the mapped interval. This haplotype spans the ABCG5/ABCG8 genes, is carried by 1.8% of the islanders, and results in a striking 100% increase of PPS in carriers. Resequencing of ABCG5 in these carriers found a D450H missense mutation along the associated haplotype. These findings exemplify the power of haplotype analysis for mapping mutations in isolated populations and specifically for dissecting effects of multiple variants of the same locus.
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No. Sentence Comment
9 Resequencing of ABCG5 in these carriers found a D450H missense mutation along the associated haplotype. These findings exemplify the power of haplotype analysis for mapping mutations in isolated populations and specifically for dissecting effects of multiple variants of the same locus.
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ABCG5 p.Asp450His 19667188:9:48
status: NEW42 Sequencing of the ABCG5/ABCG8 genes in carriers of the 526-kb haplotype revealed an ABCG5 D450H missense mutation, a plausible putative causal variant in this haplotype. These findings exemplify the power of haplotype analysis in resolving the effect of multiple variants of the same locus.
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ABCG5 p.Asp450His 19667188:42:90
status: NEW108 As shown in Fig. S3, this effort revealed an ABCG5 exon 10 missense mutation resulting in a coding change from negatively charged aspartic acid to positively charged histidine at residue 450 (D450H).
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ABCG5 p.Asp450His 19667188:108:192
status: NEW[hide] Mechanisms and genetic determinants regulating ste... J Lipid Res. 2011 Nov;52(11):1885-926. doi: 10.1194/jlr.R017855. Epub 2011 Aug 23. Calandra S, Tarugi P, Speedy HE, Dean AF, Bertolini S, Shoulders CC
Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk.
J Lipid Res. 2011 Nov;52(11):1885-926. doi: 10.1194/jlr.R017855. Epub 2011 Aug 23., [PMID:21862702]
Abstract [show]
This review integrates historical biochemical and modern genetic findings that underpin our understanding of the low-density lipoprotein (LDL) dyslipidemias that bear on human disease. These range from life-threatening conditions of infancy through severe coronary heart disease of young adulthood, to indolent disorders of middle- and old-age. We particularly focus on the biological aspects of those gene mutations and variants that impact on sterol absorption and hepatobiliary excretion via specific membrane transporter systems (NPC1L1, ABCG5/8); the incorporation of dietary sterols (MTP) and of de novo synthesized lipids (HMGCR, TRIB1) into apoB-containing lipoproteins (APOB) and their release into the circulation (ANGPTL3, SARA2, SORT1); and receptor-mediated uptake of LDL and of intestinal and hepatic-derived lipoprotein remnants (LDLR, APOB, APOE, LDLRAP1, PCSK9, IDOL). The insights gained from integrating the wealth of genetic data with biological processes have important implications for the classification of clinical and presymptomatic diagnoses of traditional LDL dyslipidemias, sitosterolemia, and newly emerging phenotypes, as well as their management through both nutritional and pharmaceutical means.
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178 Amazingly, nearly 2% of Kosrae (i.e., three large extended families and one apparently unrelated individual) carry a single missense mutation (D450H) (89), affecting the ABCG5 putative transmembrane domain.
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ABCG5 p.Asp450His 21862702:178:143
status: NEW180 ABCG8 haploinsufficiency and ABCG5 missense mutation increase net sterol absorption in a Micronesian population Noncarriers ABCG8 p.Q24HfsX8 Carriers ABCG5 p.D450H Carriers P (ANOVA) Frequency (%) - 11.1 1.8 Campesterol:cholesterol (~sterol absorption) 1.33 ± 0.52 2.00 ± 0.87 2.78 ± 1.01 <0.0001 a Lathosterol:cholesterol (~cholesterol synthesis) 1.52 ± 0.67 1.33 ± 0.55 0.84 ± 0.38 <0.0001 a Total cholesterol (mg/dl) 165.48 ± 34.35 170.20 ± 34.48 167.55 ± 34.92 0.022b Data (e.g., plasma campesterol:cholesterol ratio) are from up to 2,819 individuals (83, 89).
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ABCG5 p.Asp450His 21862702:180:158
status: NEW