ABCG8 p.Ser107*
| ClinVar: |
c.320C>G
,
p.Ser107*
D
, Pathogenic
|
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[hide] Image in cardiovascular medicine. Aortic xanthomat... Circulation. 2003 Feb 11;107(5):791. Mymin D, Wang J, Frohlich J, Hegele RA
Image in cardiovascular medicine. Aortic xanthomatosis with coronary ostial occlusion in a child homozygous for a nonsense mutation in ABCG8.
Circulation. 2003 Feb 11;107(5):791., 2003-02-11 [PMID:12578886]
Abstract [show]
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No. Sentence Comment
17 However, a novel CϾG mutation was found at the second residue of codon nucleotide 107 in exon 3 of the ABCG8 gene, which predicted premature truncation of the protein product (S107X) (Figure 2).
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ABCG8 p.Ser107* 12578886:17:182
status: NEW20 Serum cholesterol was 10.8, 11.8, and 9.2 mmol/L (416, 455, and 356 mg/dL), respectively, and serum sitosterol concentrations were 282, 447, and 184 mg/L, respectively (reference range 0 to 10 mg/L) in these relatives, who were also shown to be homozygotes for S107X.
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ABCG8 p.Ser107* 12578886:20:261
status: NEW15 However, a novel CϾG mutation was found at the second residue of codon nucleotide 107 in exon 3 of the ABCG8 gene, which predicted premature truncation of the protein product (S107X) (Figure 2).
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ABCG8 p.Ser107* 12578886:15:182
status: NEW18 Serum cholesterol was 10.8, 11.8, and 9.2 mmol/L (416, 455, and 356 mg/dL), respectively, and serum sitosterol concentrations were 282, 447, and 184 mg/L, respectively (reference range 0 to 10 mg/L) in these relatives, who were also shown to be homozygotes for S107X.
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ABCG8 p.Ser107* 12578886:18:261
status: NEW[hide] Phenotypic heterogeneity of sitosterolemia. J Lipid Res. 2004 Dec;45(12):2361-7. Epub 2004 Sep 16. Wang J, Joy T, Mymin D, Frohlich J, Hegele RA
Phenotypic heterogeneity of sitosterolemia.
J Lipid Res. 2004 Dec;45(12):2361-7. Epub 2004 Sep 16., [PMID:15375183]
Abstract [show]
Sitosterolemia is a rare autosomal recessive disorder of lipoprotein metabolism characterized by xanthomas and increased plasma concentrations of plant sterols, such as sitosterol. Causative mutations occur in either the ABCG5 or ABCG8 gene, each of which encodes a sterol half-transporter expressed in the intestine. We report five Canadian subjects with nonsense mutations in these half-transporters: four related Caucasian subjects were homozygous for the ABCG8 S107X mutation, and one unrelated Japanese-Canadian subject was homozygous for a complex insertion/deletion (I/D) mutation in ABCG5 exon 3. A female subject with each mutation was symptomatic with coronary atherosclerosis: a 5-year-old ABCG8 S107X homozygote and a 75-year-old ABCG5 exon 3 I/D homozygote; these represent the extreme ends of the spectrum of vascular involvement in sitosterolemia. The largest reductions in plasma concentrations of sitosterol and LDL-cholesterol were seen with ezetimibe or bile acid sequestrant treatment, and less dramatic reductions were seen with statin drug treatment. These findings extend the range of clinical phenotypes in sitosterolemia caused by nonsense mutations in either ABCG5 or ABCG8.
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3 We report five Canadian subjects with nonsense mutations in these half-transporters: four related Caucasian subjects were homozygous for the ABCG8 S107X mutation, and one unrelated Japanese-Canadian subject was homozygous for a complex insertion/deletion (I/D) mutation in ABCG5 exon 3.
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ABCG8 p.Ser107* 15375183:3:102
status: NEWX
ABCG8 p.Ser107* 15375183:3:147
status: VERIFIED4 A female subject with each mutation was symptomatic with coronary atherosclerosis: a 5-year-old ABCG8 S107X homozygote and a 75-year-old ABCG5 exon 3 I/D homozygote; these represent the extreme ends of the spectrum of vascular involvement in sitosterolemia.
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ABCG8 p.Ser107* 15375183:4:102
status: VERIFIED34 METHODS Study subjects Family 1: ABCG8 S107X subjects II-1 to II-4.
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ABCG8 p.Ser107* 15375183:34:39
status: VERIFIED87 RESULTS Clinical and biochemical attributes From the ABCG8 S107X kindred, subjects II-1 to II-4 each had high LDL-cholesterol and low HDL-cholesterol, with corresponding changes in apolipoprotein A-I (apoA-I) and apoB concentrations.
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ABCG8 p.Ser107* 15375183:87:59
status: VERIFIED102 Sequencing showed that the two younger siblings and the first cousin were also homozygous for the S107X mutation, whereas both parents were heterozygous.
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ABCG8 p.Ser107* 15375183:102:98
status: VERIFIED103 Additional sequence analyses showed that the ABCG8 S107X mutation was absent from the genomic DNA of 360 healthy Caucasians.
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ABCG8 p.Ser107* 15375183:103:51
status: VERIFIED108 Each of four Caucasian subjects with the ABCG8 S107X mutation, which encodes a protein that is truncated by ~80%, was ascertained under age 10 and had profound hyperlipidemia, with the index case showing marked skin manifestations and premature severe atherosclerosis with CHD.
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ABCG8 p.Ser107* 15375183:108:47
status: VERIFIEDX
ABCG8 p.Ser107* 15375183:108:111
status: NEW110 One subject with each mutation was symptomatic with coronary atherosclerosis: a 5 year old girl with the ABCG8 S107X mutation and a 75 year old woman with the ABCG5 exon 3 I/D mutation, who represent the extreme ends of the spectrum of vascular involvement in sitosterolemia.
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ABCG8 p.Ser107* 15375183:110:111
status: VERIFIED111 In the surviving ABGC8 S107X homozygotes, treatment with ezetimibe or bile acid sequestrants caused the largest reductions of plasma LDL cholesterol and sitosterol, whereas treatment with statin drugs was associated with less LDL-cholesterol reduction.
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ABCG8 p.Ser107* 15375183:111:23
status: VERIFIED123 Subjects ABCG8 S107X II-1 to II-4 demonstrated a certain degree of clinical and biochemical heterogeneity (Table 2), of which the most dramatic were the cardiac and skin manifestations in subject II-1.
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ABCG8 p.Ser107* 15375183:123:15
status: VERIFIED127 Interestingly, the parents of the proband, both of whom were heterozygotes for ABCG8 S107X, had some biochemical disparities.
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ABCG8 p.Ser107* 15375183:127:85
status: VERIFIED2 We report five Canadian subjects with nonsense mutations in these half-transporters: four related Caucasian subjects were homozygous for the ABCG8 S107X mutation, and one unrelated Japanese-Canadian subject was homozygous for a complex insertion/deletion (I/D) mutation in ABCG5 exon 3.
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ABCG8 p.Ser107* 15375183:2:147
status: NEW32 METHODS Study subjects Family 1: ABCG8 S107X subjects II-1 to II-4.
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ABCG8 p.Ser107* 15375183:32:39
status: NEW85 RESULTS Clinical and biochemical attributes From the ABCG8 S107X kindred, subjects II-1 to II-4 each had high LDL-cholesterol and low HDL-cholesterol, with corresponding changes in apolipoprotein A-I (apoA-I) and apoB concentrations.
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ABCG8 p.Ser107* 15375183:85:59
status: NEW100 Sequencing showed that the two younger siblings and the first cousin were also homozygous for the S107X mutation, whereas both parents were heterozygous.
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ABCG8 p.Ser107* 15375183:100:98
status: NEW101 Additional sequence analyses showed that the ABCG8 S107X mutation was absent from the genomic DNA of 360 healthy Caucasians.
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ABCG8 p.Ser107* 15375183:101:51
status: NEW106 Each of four Caucasian subjects with the ABCG8 S107X mutation, which encodes a protein that is truncated by 80%, was ascertained under age 10 and had profound hyperlipidemia, with the index case showing marked skin manifestations and premature severe atherosclerosis with CHD.
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ABCG8 p.Ser107* 15375183:106:47
status: NEW109 In the surviving ABGC8 S107X homozygotes, treatment with ezetimibe or bile acid sequestrants caused the largest reductions of plasma LDL cholesterol and sitosterol, whereas treatment with statin drugs was associated with less LDL-cholesterol reduction.
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ABCG8 p.Ser107* 15375183:109:23
status: NEW121 Subjects ABCG8 S107X II-1 to II-4 demonstrated a certain degree of clinical and biochemical heterogeneity (Table 2), of which the most dramatic were the cardiac and skin manifestations in subject II-1.
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ABCG8 p.Ser107* 15375183:121:15
status: NEW125 Interestingly, the parents of the proband, both of whom were heterozygotes for ABCG8 S107X, had some biochemical disparities.
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ABCG8 p.Ser107* 15375183:125:85
status: NEW[hide] Serum lipids, plant sterols, and cholesterol kinet... Am J Clin Nutr. 2012 Apr;95(4):837-44. Epub 2012 Feb 29. Myrie SB, Mymin D, Triggs-Raine B, Jones PJ
Serum lipids, plant sterols, and cholesterol kinetic responses to plant sterol supplementation in phytosterolemia heterozygotes and control individuals.
Am J Clin Nutr. 2012 Apr;95(4):837-44. Epub 2012 Feb 29., [PMID:22378727]
Abstract [show]
BACKGROUND: Plant sterol (PS) supplementation is increasingly accepted as a dietary strategy to lower plasma cholesterol concentrations. However, information is scarce about the effect of increased PS intake in potentially vulnerable groups, such as phytosterolemia heterozygotes (HET). OBJECTIVE: This study assessed the responsiveness of circulating PS and lipid concentrations and cholesterol kinetics (absorption and synthesis) to daily PS supplementation in HET (ABCG8 S107X mutation) compared with a healthy control cohort. DESIGN: A double-blind, randomized, crossover, placebo-controlled study was conducted in 10 HET and 15 control subjects. The participants had a mean (+/-SEM) age of 34 +/- 2 y and a BMI (in kg/m(2)) of 29.9 +/- 1.1 and consumed approximately 1.6 g PS or placebo capsules daily with supper for 4 wk. Cholesterol absorption and synthesis were assessed by using [(1)(3)C]cholesterol and deuterium oxide, respectively. RESULTS: Plasma LDL-cholesterol concentrations decreased (P = 0.006) in both groups after PS supplementation (HET: 2.73 +/- 0.19 mmol/L; control: 3.11 +/- 0.19 mmol/L) compared with placebo (HET: 3.12 +/- 0.20 mmol/L; control: 3.50 +/- 0.21 mmol/L), whereas PS concentrations (campesterol+beta-sitosterol) increased (P = 0.03) in both groups after PS supplementation (HET: 39.72 +/- 6.05 mumol/L; control: 24.03 +/- 1.65 mumol/L) compared with placebo (HET: 27.32 +/- 3.80 mumol/L; control: 21.12 +/- 2.05 mumol/L). Cholesterol absorption efficiency decreased (P = 0.010) by approximately 22% and approximately 17% and synthesis rates increased (P = 0.040) by approximately 20% and approximately 24% in the HET and control groups, respectively, in response to PS consumption compared with placebo. CONCLUSION: These data suggest that heterozygosity for the ABCG8 S107X mutation does not influence the action of dietary PS on circulating cholesterol concentrations but may affect sterol absorption.
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2 Objective: This study assessed the responsiveness of circulating PS and lipid concentrations and cholesterol kinetics (absorption and synthesis) to daily PS supplementation in HET (ABCG8 S107X mutation) compared with a healthy control cohort.
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ABCG8 p.Ser107* 22378727:2:187
status: NEW8 Conclusion: These data suggest that heterozygosity for the ABCG8 S107X mutation does not influence the action of dietary PS on circulating cholesterol concentrations but may affect sterol absorption.
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ABCG8 p.Ser107* 22378727:8:65
status: NEW35 These volunteers were related to a proband reported by Mymin et al (17, 18) to have the ABCG8 S107X mutation.
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ABCG8 p.Ser107* 22378727:35:94
status: NEW36 Thus, genotyping for the ABCG8 S107X mutation was used to identify phytosterolemia heterozygotes (HET; n = 10) and control subjects (control; n = 15).
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ABCG8 p.Ser107* 22378727:36:31
status: NEW37 Individuals homozygous for the ABCG8 S107X mutation or with thyroid disease, diabetes mellitus, kidney disease, or liver disease were excluded from the study.
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ABCG8 p.Ser107* 22378727:37:37
status: NEW173 In the current study, heterozygosity for the ABCG8 S107X mutation was found to be associated with increased plasma PS (campesterol+b-sitosterol) concentrations and lower lathosterol concentrations; however, using stable-isotope techniques we found no significant effects on cholesterol absorption or fractional synthesis in the HET group compared with the control group.
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ABCG8 p.Ser107* 22378727:173:51
status: NEW174 In conclusion, the current work suggests that, although the ABCG8 S107X heterozygous mutation affected plasma PS concentrations, there seems to be a lack of effect of this mutation on cholesterol metabolism.
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ABCG8 p.Ser107* 22378727:174:66
status: NEW[hide] Ezetimibe reduces plant sterol accumulation and fa... J Pediatr. 2015 Jan;166(1):125-31. doi: 10.1016/j.jpeds.2014.08.069. Epub 2014 Oct 16. Othman RA, Myrie SB, Mymin D, Merkens LS, Roullet JB, Steiner RD, Jones PJ
Ezetimibe reduces plant sterol accumulation and favorably increases platelet count in sitosterolemia.
J Pediatr. 2015 Jan;166(1):125-31. doi: 10.1016/j.jpeds.2014.08.069. Epub 2014 Oct 16., [PMID:25444527]
Abstract [show]
OBJECTIVE: To assess if ezetimibe (EZE), a sterol-absorption inhibitor, improves platelet (PLT) count and size relative to its effect on plasma plant sterol (PS) in patients with sitosterolemia (STSL). STUDY DESIGN: Patients with STSL (5 males, 3 females, 16-56 years of age) receiving EZE intervention as part of their routine care participated in this study. EZE was discontinued for 14 weeks (off) and then resumed for another 14 weeks (on). Hematology variables along with plasma and red blood cells (RBC) PS and total cholesterol (TC) levels were measured at the end of each phase. RESULTS: EZE increased PLT count (23% +/- 9%) and decreased mean PLT volume (MPV; 10% +/- 3%, all P < .05). In patients off EZE, PLT counts inversely correlated (r = -0.96 and r = -0.91, all P < .01) with plasma and RBC PS to TC ratio (PS/TC), and MPV positively correlated (r = 0.91, P = .03 and r = 0.93, P = .02) with plasma and RBC PS/TC. EZE reduced plasma and RBC sitosterol (-35% +/- 4% and -28% +/- 3%), total PS (-37% +/- 4% and -28% +/- 3%, all P < .0001) levels, and PS/TC (-27% +/- 4% and -28% +/- 4%, P < .01). CONCLUSIONS: EZE reduces plasma and RBC PS levels, while increasing PLT count and decreasing MPV, and thereby may reduce the risk for bleeding in STSL. Plasma PS levels and ABCG5/ABCG8 genes should be analyzed in patients with unexplained hematologic abnormalities.
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No. Sentence Comment
24 All patients were identified as having homozygous ABCG8 S107X mutation (NM_022437.2:c.320C>G) and are related to a proband previously reported by Mymin et al21,22 and Chong et al.23 All procedures involving human patients were approved by the University of Manitoba Biomedical Ethics board and written informed consent was obtained from all patients.
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ABCG8 p.Ser107* 25444527:24:56
status: NEW