ABCA1 p.Met640Leu
| Predicted by SNAP2: | A: D (63%), C: D (59%), D: D (85%), E: D (85%), F: N (78%), G: D (66%), H: D (71%), I: N (66%), K: D (85%), L: N (87%), N: D (80%), P: D (91%), Q: D (71%), R: D (85%), S: D (80%), T: D (71%), V: D (53%), W: D (75%), Y: D (53%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: N, G: D, H: D, I: N, K: D, L: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: N, |
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[hide] Increased risk of coronary artery disease in Cauca... Biochim Biophys Acta. 2012 Mar;1821(3):416-24. doi: 10.1016/j.bbalip.2011.08.006. Epub 2011 Aug 19. Tietjen I, Hovingh GK, Singaraja R, Radomski C, McEwen J, Chan E, Mattice M, Legendre A, Kastelein JJ, Hayden MR
Increased risk of coronary artery disease in Caucasians with extremely low HDL cholesterol due to mutations in ABCA1, APOA1, and LCAT.
Biochim Biophys Acta. 2012 Mar;1821(3):416-24. doi: 10.1016/j.bbalip.2011.08.006. Epub 2011 Aug 19., [PMID:21875686]
Abstract [show]
Mutations in ABCA1, APOA1, and LCAT reduce HDL cholesterol (HDLc) in humans. However, the prevalence of these mutations and their relative effects on HDLc reduction and risk of coronary artery disease (CAD) are less clear. Here we searched for ABCA1, APOA1, and LCAT mutations in 178 unrelated probands with HDLc <10th percentile but no other major lipid abnormalities, including 89 with >/=1 first-degree relative with low HDLc (familial probands) and 89 where familial status of low HDLc is uncertain (unknown probands). Mutations were most frequent in LCAT (15.7%), followed by ABCA1 (9.0%) and APOA1 (4.5%), and were found in 42.7% of familial but only 14.6% of unknown probands (p=2.44 *10(-5)). Interestingly, only 16 of 24 (66.7%) mutations assessed in families conferred an average HDLc <10th percentile. Furthermore, only mutation carriers with HDLc <5th percentile had elevated risk of CAD (odds ratio (OR)=2.26 for 34 ABCA1 mutation carriers vs. 149 total first-degree relative controls, p=0.05; OR=2.50 for 26 APOA1 mutation carriers, p=0.04; OR=3.44 for 38 LCAT mutation carriers, p=1.1 *10(-3)). These observations show that mutations in ABCA1, APOA1, and LCAT are sufficient to explain >40% of familial hypoalphalipoproteinemia in this cohort. Moreover, individuals with mutations and large reductions in HDLc have increased risk of CAD. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).
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No. Sentence Comment
117 COOHA B T929I H2N R587W B A M1091T C1477R K776N N935S S1181F IVS24+1 G>C V2244I R282X D571G M640L S930F M968T R1615WIVS16-5 CA>del ABCA1 Transmembrane domain ATP-binding domain Q597R A) AA 1 AA 267 K130del L202P 74 90 98 112 122 145 167 189 211 215 233 253 APOA1 Negative charge domain Alpha-helix E222K E134DT37M 140 178 206 41127 104 121 165 200 229 360 391 Y135N V246F 127 206 369 401 Catalytic triad R322C L338H V371MV52M Y107X A117T T147I V333M Phe Leu Asp His AA 1 AA 440 R159Q I202T LCAT Alpha helixBeta sheet B) 419I.Tietjenetal./BiochimicaetBiophysicaActa1821(2012)416-424 3.4.
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ABCA1 p.Met640Leu 21875686:117:92
status: NEW[hide] Segregation of LIPG, CETP, and GALNT2 Mutations in... PLoS One. 2012;7(8):e37437. Epub 2012 Aug 27. Tietjen I, Hovingh GK, Singaraja RR, Radomski C, Barhdadi A, McEwen J, Chan E, Mattice M, Legendre A, Franchini PL, Dube MP, Kastelein JJ, Hayden MR
Segregation of LIPG, CETP, and GALNT2 Mutations in Caucasian Families with Extremely High HDL Cholesterol.
PLoS One. 2012;7(8):e37437. Epub 2012 Aug 27., [PMID:22952570]
Abstract [show]
To date, few mutations are described to underlie highly-elevated HDLc levels in families. Here we sequenced the coding regions and adjacent sequence of the LIPG, CETP, and GALNT2 genes in 171 unrelated Dutch Caucasian probands with HDLc>/=90th percentile and analyzed segregation of mutations with lipid phenotypes in family members. In these probands, mutations were most frequent in LIPG (12.9%) followed by GALNT2 (2.3%) and CETP (0.6%). A total of 6 of 10 mutations in these three genes were novel (60.0%), and mutations segregated with elevated HDLc in families. Interestingly, the LIPG mutations N396S and R476W, which usually result in elevated HDLc, were unexpectedly found in 6 probands with low HDLc (i.e., </=10th percentile). However, 5 of these probands also carried mutations in ABCA1, LCAT, or LPL. Finally, no CETP and GALNT2 mutations were found in 136 unrelated probands with low HDLc. Taken together, we show that rare coding and splicing mutations in LIPG, CETP, and GALNT2 are enriched in persons with hyperalphalipoproteinemia and segregate with elevated HDLc in families. Moreover, LIPG mutations do not overcome low HDLc in individuals with ABCA1 and possibly LCAT and LPL mutations, indicating that LIPG affects HDLc levels downstream of these proteins.
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No. Sentence Comment
157 Vertebrate conservation Predicted effect Position (hg18) Effect ABCA1 Chr9:106631215 T.A M640L No [47] Completely conserved Possibly damaging (Polyphen-2) Chr9:106619433 C.G IVS24+1G.C No [15] Completely conserved Abolishes splice donor site (Spliceview) Chr9:106618441 G.A S1181F No [48] Completely conserved Probably damaging (Polyphen-2) LCAT Chr16:66534158 G.A T147I No [12] Completely conserved Possibly damaging (Polyphen-2) LPL Chr8:19857809 A.G N318S No [13] Ser tolerated Reduced HDLc (Reymer et al., 1995) doi:10.1371/journal.pone.0037437.t005 result in large increases and reductions in HDLc, respectively [13,29,30], which further support a role for GALNT2 loss-of- function mutations in HDLc elevation.
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ABCA1 p.Met640Leu 22952570:157:89
status: NEW155 Vertebrate conservation Predicted effect Position (hg18) Effect ABCA1 Chr9:106631215 T.A M640L No [47] Completely conserved Possibly damaging (Polyphen-2) Chr9:106619433 C.G IVS24+1G.C No [15] Completely conserved Abolishes splice donor site (Spliceview) Chr9:106618441 G.A S1181F No [48] Completely conserved Probably damaging (Polyphen-2) LCAT Chr16:66534158 G.A T147I No [12] Completely conserved Possibly damaging (Polyphen-2) LPL Chr8:19857809 A.G N318S No [13] Ser tolerated Reduced HDLc (Reymer et al., 1995) doi:10.1371/journal.pone.0037437.t005 result in large increases and reductions in HDLc, respectively [13,29,30], which further support a role for GALNT2 loss-of-function mutations in HDLc elevation.
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ABCA1 p.Met640Leu 22952570:155:89
status: NEW