ABCMdb

ABCG5 p.Arg389His

ClinVar:	c.1166G>A , p.Arg389His D , Pathogenic
Predicted by SNAP2:	A: D (95%), C: D (95%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), H: D (95%), I: D (95%), K: D (95%), L: D (95%), M: D (95%), N: D (95%), P: D (95%), Q: D (95%), S: D (95%), T: D (95%), V: D (95%), W: D (95%), Y: D (95%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: N, I: D, K: N, L: D, M: D, N: D, P: D, Q: N, S: D, T: D, V: D, W: D, Y: D,

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[hide] Identification of a gene, ABCG5, important in the ... Nat Genet. 2001 Jan;27(1):79-83. Lee MH, Lu K, Hazard S, Yu H, Shulenin S, Hidaka H, Kojima H, Allikmets R, Sakuma N, Pegoraro R, Srivastava AK, Salen G, Dean M, Patel SB
Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption.
Nat Genet. 2001 Jan;27(1):79-83., [PMID:11138003]

Abstract [show]
The molecular mechanisms regulating the amount of dietary cholesterol retained in the body, as well as the body's ability to exclude selectively other dietary sterols, are poorly understood. An average western diet will contain about 250-500 mg of dietary cholesterol and about 200-400 mg of non-cholesterol sterols. About 50-60% of the dietary cholesterol is absorbed and retained by the normal human body, but less than 1% of the non-cholesterol sterols are retained. Thus, there exists a subtle mechanism that allows the body to distinguish between cholesterol and non-cholesterol sterols. In sitosterolemia, a rare autosomal recessive disorder, affected individuals hyperabsorb not only cholesterol but also all other sterols, including plant and shellfish sterols from the intestine. The major plant sterol species is sitosterol; hence the name of the disorder. Consequently, patients with this disease have very high levels of plant sterols in the plasma and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. We previously mapped the STSL locus to human chromosome 2p21 and further localized it to a region of less than 2 cM bounded by markers D2S2294 and D2S2291 (M.-H.L. et al., manuscript submitted). We now report that a new member of the ABC transporter family, ABCG5, is mutant in nine unrelated sitosterolemia patients.

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No. Sentence Comment
29 We identified five point mutations: R243X (exon 6, proband 25), R389H (exon 9, probands 46, 113 and 146), R408X (exon 9, proband 140), R419H (exon 9, probands 40 and 132) and R419P (exon 9, proband 157) (Fig. 2a). Login to comment
35 Mutations resulting in R243X, R408X, R389H and R419H/P altered cleavage sites of restriction enzymes. Login to comment
50 Additionally, the first BstUI site is altered by mutation R389H (middle right panels). Login to comment
62 letter 80 nature genetics • volume 27 • january 2001 A G G A A C T G A A T T Arg Asn stop Ile C G A Arg A G G A A C A T Tnormal proband 25 T G AG T C A G CC G G Arg Val stop Ser C G A Arg C G GG T C A G Cnormal proband 140 100 200 300 400 bp 500 M C2C2+ 146 C1+ 113 132 140 41 46 63 M 100 200 300 400 500 bp M 41 46 63 113 132 140 146 C1+ C2+ C2- M AlwNI CAGNNNCTG 1 272 normal 135 141 proband 25 bp bp Ava I CPyCGPuG normal 199 109 proband 140 166 33 109 100 200 300 400 bp 500 100 200 300 400 500 M 22 23 24 25 26 27 C1+ C2+ M bp C2- 500 22 23 M 155 157 158 159 160 C1+ C2+ C2- M 155 156 4000 C C C G T AG A CC A G Gln Asp Pro Val C G C Arg C A G G A C G T A Proband 157 Normal BstUI CGCG 112 196 probands 41, 132, 157 92 normal 112 104 probands 46, 113, 146 204 104 normal 112 10492 exon 6 R243* exon 9 R408* exon 9 R389H exon 9 R419P BstUI CGCG bp bp bp bp bp bp proband 146 C T TC T CC A TA C G Thr His Leu Leu Arg normal C T TC T CC G TA C G 1 GCTCCGGGAA AACCAC---- CTGGGGACCT T--------- -------CCT 50 wild-type 1 GCTCCGGGAA AACCACGCTG CTGGACGCCA TGTCCGGGAG GCTGGGGCGC 50 51 GGGGGGTCCT TCCTGGGGGA GGTGTATGTG AACGGCCGGG CGCTGCGCCG 100 51 GCGGGGACCT TCCTGGGGGA GGTGTATGTG AACGGCCGGG CGCTGCGCCG 100 proband wild-type proband wild-type proband 101 GGAGCAGTTC CAGGACTGCT TCTCCTACGT CCTGCAG... .......... 150101 GGAGCAGTTC CAGGACTGCT TCTCCTACGT CCTGCAG... .......... 150 M wt+mut 63 64 65 66 67 C1 C2 M 61 62 mut wt wt + mut 200bp 400bp 500bp 1 2 3 4 5 6 7 8 9 10 Table 1 • Frequency of nucleotide changes in unrelated Japanese and North Americans of European descent Nucleotide change Predicted consequences Carrier frequency Restriction endonuclease changes C167T P9P not screened gain of BstNI site ∆20 bp at 402 frameshift & truncated protein no carriers in 55 Japanese controls - C867T R243X not screened gain of AlwNI site G1306A R389H no carriers in 145 Japanese and 156 Caucasians Loss of BstUI site C1362T R408X not screened loss of AvaI site G1396A R419H no carriers in 145 Japanese and 156 Caucasians Loss of BstUI site G1396C R419P no carriers in 145 Japanese and 156 Caucasians Loss of BstUI site C1950G Q604E 36% carriers in Caucasians loss of SmlI site Mutations (R243X, R408X, and R419H/P) or polymorphism Q604E were screened in unrelated Japanese and North Americans of European descent, using the restriction assays described in Fig. 2. Login to comment

[hide] Genetic basis of sitosterolemia. Curr Opin Lipidol. 2001 Apr;12(2):141-9. Lee MH, Lu K, Patel SB
Genetic basis of sitosterolemia.
Curr Opin Lipidol. 2001 Apr;12(2):141-9., [PMID:11264985]

Abstract [show]
The molecular mechanisms regulating the amount of dietary cholesterol retained by the body, as well as the body's ability to exclude other dietary sterols selectively, are poorly understood. An average Western diet will contain approximately 250-500 mg of dietary cholesterol and approximately 200-400 mg of non-cholesterol sterols, of which plant sterols are the major constituents. Approximately 50-60% of dietary cholesterol is absorbed and retained by the normal human body, but less than 1% of the non-cholesterol sterols are retained. There thus exists a subtle mechanism that allows the body to distinguish between cholesterol and non-cholesterol sterols. In sitosterolemia, a rare autosomal recessive disorder, affected individuals hyperabsorb and retain not only cholesterol but also all other sterols, including plant and shellfish sterols from the intestine. Consequently, patients with this disease have very high levels of plant sterols in the plasma, and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. The STSL locus has been mapped to human chromosome 2p21. Mutations in two tandem ABC genes, ABCG5 and ABCG8, encoding sterolin-1 and -2, respectively, are now known to be mutant in sitosterolemia. The identification of these genes should now lead to a better understanding of the molecular mechanism(s) governing the highly selective absorption and retention of cholesterol by the body. Indeed, it is the very existence of this disease that has given credence to the hypothesis that there is a molecular pathway that regulates dietary cholesterol absorption and sterol excretion by the body.

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108 Mutations in ABCG5 and ABCG8 in sitosterolemia Patients Nationality/ethnicity ABCG5 ABCG8 4 US/Caucasian Arg412X Trp361X 9 US/Caucasian Arg543Ser Gln172X 56* US/Caucasian Tyr658X Trp361X 60 US/Caucasian Trp361X ± 90* US/Caucasian Trp361X Trp361X 94 US/Caucasian Trp361X Arg184His 120 US/Caucasian Leu501Pro Trp361X 125 US/Caucasian Trp361X Trp361X 128 US/Caucasian Leu596Arg ± 32 SA Caucasian Arg121X Arg121X 98 Dutch Caucasian Gly574Glu Trp361X 102* US/Caucasian Trp361X ± 135 Columbian/Caucasian Trp536X Trp536X 20 Finnish Trp361X Trp361X 116 Norwegian Trp36X Trp361X 84* US/Amish/Mennonite Gly574Arg Gly574Arg 108 US/Amish/Mennonite Gly574Arg Gly574Arg 25 SA/Asian Arg243X Arg243X 40 Japanese Arg419His Arg419His 46 Japanese Arg389His Arg389His 63 Japanese del Exon 3 del Exon 3 113 Japanese Arg389His Arg389His 132 Japanese Arg419His ± 140 Japanese Arg408X Arg408X 146 Japanese Arg389His Arg389His 157 US/Caucasian Arg419Pro Arg419Pro 15 US/Caucasian ± ± 143 SA/Indian Asian ± ± Arg121X Arg164X 149 African American Glu145Gln ± 1* German/Swiss Trp361X Trp361X 2* US/Amish Gly574Arg Gly574Arg 3* US/Caucasian Trp361X Tyr658X 5* US/Caucasian Trp361X Arg412X 6* US/Caucasian Leu596Arg ± 7 US/Hispanic Arg412X del547C4191X 8* NZ/Caucasian Trp361X ± 4 Chinese Arg263Gln Pro231Thr 9 Chinese Arg408X ± This is a compilation of the mutations identified in ABCG5 and ABCG8. Login to comment

[hide] Missense mutations in ABCG5 and ABCG8 disrupt hete... J Biol Chem. 2004 Jun 4;279(23):24881-8. Epub 2004 Mar 30. Graf GA, Cohen JC, Hobbs HH
Missense mutations in ABCG5 and ABCG8 disrupt heterodimerization and trafficking.
J Biol Chem. 2004 Jun 4;279(23):24881-8. Epub 2004 Mar 30., 2004-06-04 [PMID:15054092]

Abstract [show]
Mutations in ABCG5 (G5) or ABCG8 (G8) cause sitosterolemia, an autosomal recessive disease characterized by sterol accumulation and premature atherosclerosis. G5 and G8 are ATP-binding cassette (ABC) half-transporters that must heterodimerize to move to the apical surface of cells. We examined the role of N-linked glycans in the formation of the G5/G8 heterodimer to gain insight into the determinants of folding and trafficking of these proteins. Site-directed mutagenesis revealed that two asparagine residues (Asn(585) and Asn(592)) are glycosylated in G5 and that G8 has a single N-linked glycan attached to Asn(619). N-Linked glycosylation of G8 was required for efficient trafficking of the G5/G8 heterodimer, but mutations that abolished glycosylation of G5 did not prevent trafficking of the heterodimer. Both G5 and G8 are bound by the lectin chaperone, calnexin, suggesting that the calnexin cycle may facilitate folding of the G5/G8 heterodimer. To determine the effects of 13 disease-causing missense mutations in G5 and G8 on formation and trafficking of the G5/G8 heterodimer, mutant forms of the half-transporters were expressed in CHO-K1 cells. All 13 mutations reduced trafficking of the G5/G8 heterodimer from the endoplasmic reticulum to the Golgi complex, and most prevented the formation of stable heterodimers between G5 and G8. We conclude that the majority of the molecular defects in G5 and G8 that cause sitosterolemia impair transport of the sterol transporter to the cell surface.

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203 No mature G5 was present in cells expressing G5 with the R389H, R419H, or N437K mutations. Login to comment
202 No mature G5 was present in cells expressing G5 with the R389H, R419H, or N437K mutations. Login to comment

[hide] Clinical observations, molecular genetic analysis,... J Inherit Metab Dis. 2010 Aug;33(4):437-43. Epub 2010 Jun 3. Niu DM, Chong KW, Hsu JH, Wu TJ, Yu HC, Huang CH, Lo MY, Kwok CF, Kratz LE, Ho LT
Clinical observations, molecular genetic analysis, and treatment of sitosterolemia in infants and children.
J Inherit Metab Dis. 2010 Aug;33(4):437-43. Epub 2010 Jun 3., [PMID:20521169]

Abstract [show]
The clinical observation and treatment of young children with sitosterolemia has rarely been reported. We report clinical, biochemical, and molecular genetic observations and treatment outcomes for five Chinese children from four separate families presenting with sitosterolemia in whom we identified two new (Y329X, G269R) and three known (R446X, N437K, R389H) mutations in the ABCG5 gene. The R389H mutation was found in 50% of alleles. Three of these five patients received cholestyramine therapy with a very good response. However, all patients discontinued this therapy because of poor compliance. Finally, all patients were on ezetimibe therapy and had satisfactory total serum cholesterol levels, though their plant sterol levels were still higher than normal. Another noteworthy finding is that a female infant had a serum cholesterol level of 654 mg/dl at 7 months of age, despite being breast fed (with very tiny amounts of plant sterols) since birth and undergoing 4 months of ezetimibe administration. Although she failed to respond to ezetimibe during this period, she did show improvement when the therapy was started again at 2 years of age. It is possible that another 23-month-old female patient also responded more slowly to ezetimibe treatment than older patients.

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1 We report clinical, biochemical, and molecular genetic observations and treatment outcomes for five Chinese children from four separate families presenting with sitosterolemia in whom we identified two new (Y329X, G269R) and three known (R446X, N437K, R389H) mutations in the ABCG5 gene. Login to comment
2 The R389H mutation was found in 50% of alleles. Login to comment
23 Large peaks of serum plant sterols were identified by nuclear magnetic resonance (NMR) spectroscopy, but the exact concentrations of these sterols were unable to be Table 1 Baseline lipid profiles, liver enzymes, and blood cell counts of each study patient Patient no Normal values 1 2 3 4 5 Age at diagnosis 8 years 18 months 3 months 23 months 12 years Mutation (ABCG5) Y329X R389H R389H R389H R389H N437K R446X R446X R389H G269R Initial diagnostic data Cholesterol, mg/dl Total 125-240 427 705 402 640 343 Low-density-lipoprotein 60-150 346 565 304 519 263 High-density-lipoprotein 35-84 59 64 42 64 50 Total triglycerides, mg/dl 20-200 111 149 395a 98 98 Liver enzymes Alanine transaminase, U/l 5-45 10 13 45 15 44 Aspartate aminotransferase, U/l 15-55 19 31 100 31 37 Blood count Erythrocytes, count/µl 3.7×109 -5.3×109 3.35×109 4.25×109 3.98×109 4.49×109 4.46×109 Hemoglobin, g/dl 11.5-15.5 9.8 11.8 11 12.7 12.9 Mean corpuscular volume, fl 80-95 88.5 89.0 80.6 80.2 86 White blood cells, count/µl 4,500-17,500 7,200 6,900 6,700 11,200 5,200 Platelets, count/mm3 150×106 -350×106 211×106 289×106 506×106 566×106 293×106 After ezetimibe therapy Age at plant sterols analysis NA 5 years 3 years 3 year 13 year Duration of ezetimibe treatment NA 3 years 1 year 1 year 6 months Cholesterol, total (mg/dl) 125-240 NA 181 208 223 193 Sitosterol mg/dlb 0.216±0.220 (SD)c NA 7.10 9.17 7.07 6.14 Campesterol mg/dlb 0.309±0.165 (SD)c NA 3.79 4.78 4.04 4.22 NA not available a In the nonfasting state b Plant sterols were measured by gas chromatography/mass spectrometry, as previously described (Kwiterovich et al. 2003). Login to comment
79 Patients 2 and 3 also had compound heterozygous mutations (R389H and R446X). Login to comment
80 R389H (c.1166G>A), located in exon 9, caused an arginine to be replaced by a histidine at codon 389. Login to comment
84 Patient 4 had a homozygous mutation, R389H. Login to comment
85 Patient 5 had compound heterozygous mutations, p.R389H and p.G269R. Login to comment

[hide] Current therapy for patients with sitosterolemia--... J Atheroscler Thromb. 2010 Sep 30;17(9):891-900. Epub 2010 Jun 11. Tsubakio-Yamamoto K, Nishida M, Nakagawa-Toyama Y, Masuda D, Ohama T, Yamashita S
Current therapy for patients with sitosterolemia--effect of ezetimibe on plant sterol metabolism.
J Atheroscler Thromb. 2010 Sep 30;17(9):891-900. Epub 2010 Jun 11., 2010-09-30 [PMID:20543520]

Abstract [show]
Sitosterolemia is a rare, autosomal recessive inherited sterol storage disease associated with high tissue and serum plant sterol concentrations, caused by mutations in the adenosine triphosphate-bind-ing cassette (ABC) transporter ABCG5 or ABCG8 genes. Markedly increased serum concentration of plant sterols. such as sitosterol and campesterol, cause premature atherosclerosis and massive xanthomas. Hitherto known treatments for sitosterolemia, including a low-sterol diet, bile-salt binding resins, ileal bypass surgery and low density lipoprotein (LDL) apheresis have not yielded sufficient reduction of serum plant sterol levels and many patients show a sustained elevation of plant sterol levels, subsequently developing premature atherosclerotic cardiovascular diseases. Ezetimibe, an inhibitor of intestinal cholesterol absorption through its binding to Niemann-Pick C1-like 1 (NPC1L1), has been widely used for decreasing serum LDL-cholesterol levels in patients with hypercholesterolemia. Ezetimibe also reduces the gastrointestinal absorption of plant sterols, thereby also lowering the serum concentrations of plant sterols. This pharmacological property of ezetimibe shows its potential as a novel effective therapy for sitosterolemia. In the current review, we discuss the current therapy for patients with sitosterolemia and present two Japanese adolescent patients with this disease, one of whom underwent percutaneous coronary intervention for accelerated coronary atherosclerosis. Ezetimibe administration in addition to conventional drug therapy successfully reduced serum sitosterol levels by 51.3% and 48.9%, respectively, in the two patients, demonstrating ezetimibe as a novel and potent treatment agent for sitosterolemia that could work additively with conventional drug therapy.

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108 Location of the gene mutation and hematological/ biochemical laboratory data in case 1 (at the time of PCI) and case 2 (at the first visit) Case 1 Case 2 ABCG5 mutation WBC (/ L) RBC ( 104 / L) Hemoglobin (g/dL) Platelet ( 104 / L) AST (IU/L) ALT (IU/L) CRP (mg/dL) Total Cholesterol (mg/dL) LDL Cholesterol (mg/dL) HDL Cholesterol (mg/dL) Triglyceride (mg/dL) Sitosterol ( g/mL) Campesterol ( g/mL) Stigmasterol ( g/mL) A1756C (R550S) G1362A (R419H) 7,610 382 9.8 18.5 14 16 0.3 172 87 67 121 87.8 48.8 4.0 G1306A (R389H) C1949 (Q604E) 6,370 385 10.9 12.5 29 26 1.0 289 229 85 172 88.5 84.5 7.2 Fig.3. Login to comment

[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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115 In this ethnic group, ABCG5 exon 9 is most commonly affected, and the most common mutation is R389H. Login to comment
113 In this ethnic group, ABCG5 exon 9 is most commonly affected, and the most common mutation is R389H. Login to comment

[hide] Genetic disorders associated with ATP binding cass... Mol Genet Metab. 2002 Sep-Oct;77(1-2):13-20. Burris TP, Eacho PI, Cao G
Genetic disorders associated with ATP binding cassette cholesterol transporters.
Mol Genet Metab. 2002 Sep-Oct;77(1-2):13-20., [PMID:12359125]

Abstract [show]
Coronary artery disease is the most prevalent form of mortality and morbidity in Western countries. Studies in the last several decades have identified high LDL cholesterol and low HDL cholesterol as major risk factors leading to the disease. Human genetic studies have provided significant insight into the regulation of lipoprotein metabolism. In the last several years, the genes associated with several rare genetic diseases of lipid metabolism have been revealed. These landmark discoveries that identified mutant ABC cholesterol transporters as the underlying causes of these genetic disorders have paved the way for better understanding of the cellular cholesterol transport process and HDL biogenesis. This summary provides an overview and discussion of the most recent progress that includes molecular mechanism and regulation of cholesterol transport mediated by these ABC transporters.

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112 Regulation of ABC cholesterol transporters by LXR/ RXR heterodimer One feature of ABC transporters is that they are usually feed back/forward regulated by their own sub-Table 2 Summary of mutations described in sitosterolemia Nucleotide sequence change Protein sequence change ABC transporters References 402Del Truncated protein ABCG5 [12] C867T R243X ABCG5 [12] G1306A R389H ABCG5 [12] C1362T R408X ABCG5 [11,12] G1396A R419H ABCG5 [12] G1396C R419P ABCG5 [12] 547Del P231T ABCG8 [11] A691C 191Stop ABCG8 [11] G788A R263Q ABCG8 [11] G1083A W361Stop ABCG8 [11] C1234T R412stop ABCG8 [11] G1720A G574R ABCG8 [11] T1787G L596R ABCG8 [11] C1974G Y658Stop ABCG8 [11] strates at the level of transcription. Login to comment

[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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169 A few of the mutations are over-represented in certain ethnic groups (e.g., ABCG5, R389H in Japanese, Chinese (71, 85), ABCG8, W361X in Europeans (45, 59, 81), implying founder effects, but otherwise, each mutation is confined to one or two kindred. Login to comment

[hide] Increased plasma plant sterol concentrations and a... Eur J Med Genet. 2011 Jul-Aug;54(4):e458-60. Epub 2011 May 23. Keller S, Prechtl D, Aslanidis C, Ceglarek U, Thiery J, Schmitz G, Jahreis G
Increased plasma plant sterol concentrations and a heterozygous amino acid exchange in ATP binding cassette transporter ABCG5: a case report.
Eur J Med Genet. 2011 Jul-Aug;54(4):e458-60. Epub 2011 May 23., [PMID:21664501]

Abstract [show]
Whilst conducting a scientific study, an elevated plasma plant sterol concentration of 3.07 mg/dL was established in one proband. Similar levels found in his mothers plasma (2.73 mg/dL) were suggestive of a heterozygous sitosterolemia. The resulting gene analysis for ATP binding cassette transporter G5/G8 (ABCG5/G8) revealed a heterozygous polymorphism in ABCG8 (Thr400Lys, rs4148217), which the proband had inherited from his father. However, a heterozygous amino acid exchange (Arg406Gln) in exon 9 of ABCG5 was revealed, which was inherited from his mother. Although not sufficient evidence exists to regard this sequence variation as a mutation, this previously unreleased sequence variation occurred in a "hot spot" area for sitosterolemia of the ABCG5 gene (exon 9) and the similar increased plasma plant sterol concentrations of the heterozygous mother contribute to the notion, that this very likely presents an inactivating mutation.

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57 In addition to splicing, insertions, deletion, and complete rearrangement of the ABCG5 gene,13 mutations with an amino acid exchange resulting in sitosterolemia are published (Gln22Term [14], Glu77Term [15], Glu146Gln [16], Arg243Term [17], Gly269Arg, Tyr329Term [7], Arg389His, Arg408Term, Arg419His, Arg419Pro [17], Asn437Lys [18], Arg446Term [1], Arg550Ser [16]). Login to comment
58 Five of the 13 mutations are located in exon 9 of the ABCG5 gene (Arg389His, Arg408Term, Arg419His, Arg419Pro, Asn437Lys) corresponding to our findings regarding the amino acid exchange Arg406Gln. Login to comment

[hide] Two genes that map to the STSL locus cause sitoste... Am J Hum Genet. 2001 Aug;69(2):278-90. Epub 2001 Jul 9. Lu K, Lee MH, Hazard S, Brooks-Wilson A, Hidaka H, Kojima H, Ose L, Stalenhoef AF, Mietinnen T, Bjorkhem I, Bruckert E, Pandya A, Brewer HB Jr, Salen G, Dean M, Srivastava A, Patel SB
Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively.
Am J Hum Genet. 2001 Aug;69(2):278-90. Epub 2001 Jul 9., [PMID:11452359]

Abstract [show]
Sitosterolemia is a rare autosomal recessive disorder characterized by (a) intestinal hyperabsorption of all sterols, including cholesterol and plant and shellfish sterols, and (b) impaired ability to excrete sterols into bile. Patients with this disease have expanded body pools of cholesterol and very elevated plasma plant-sterol species and frequently develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. In previous studies, we have mapped the STSL locus to human chromosome 2p21. Recently, we reported that a novel member of the ABC-transporter family, named "sterolin-1" and encoded by ABCG5, is mutated in 9 unrelated families with sitosterolemia; in the remaining 25 families, no mutations in sterolin-1 could be identified. We identified another ABC transporter, located <400 bp upstream of sterolin-1, in the opposite orientation. Mutational analyses revealed that this highly homologous protein, termed "sterolin-2" and encoded by ABCG8, is mutated in the remaining pedigrees. Thus, two highly homologous genes, located in a head-to-head configuration on chromosome 2p21, are involved as causes of sitosterolemia. These studies indicate that both sterolin-1 and sterolin-2 are indispensable for the regulation of sterol absorption and excretion. Identification of sterolin-1 and sterolin-2 as critical players in the regulation of dietary-sterol absorption and excretion identifies a new pathway of sterol transport.

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134 A human full- Table 2 Compilation of Mutations in ABCG5 and ABCG8 PATIENT (NATIONALITY/ETHNICITY) MUTATIONS IN ABCG5a ABCG8b 4 (U.S./white) Trp361X (1173GrA) / Arg412X (1324CrT) 9 (U.S./white) Arg543Ser (1719GrT) / Gln172X (604CrT) 56c (U.S./white) Trp361X (1173GrA) / Tyr658X (2064CrG) 60 (U.S./white) Trp361X (1173GrA) / IVS1 -2 ArG 90c (U.S./white) Trp361X (1173GrA) / Trp361X (1173GrA) 94 (U.S./white) Trp361X (1173GrA) / Arg184His (641GrA) 120 (U.S./white) Trp361X (1173GrA) / Leu501Pro (1592TrC) 125 (U.S./white) Trp361X (1173GrA) / Trp361X (1173GrA) 128 (U.S./white) Leu596Arg (1877TrG) / IVS1 -2 ArG 172 (U.S./white) Trp361X (1173GrA) / Tyr658Stop (2064CrG) 166c (U.S./white) Trp361X (1173GrA) / Arg412X (1324CrT) 32 (SA/white) Arg121X (451CrT) / Arg121X (451CrT) 98 (Dutch/white) Trp361X (1173GrA) / Gly574Glu (1811GrA) 102c,d (U.S./white) Trp361X (1173GrA) / … 84c (U.S./Amish-Mennonite) Gly574Arg (1810GrA) / Gly574Arg (1810GrA) 108c (U.S./Amish-Mennonite) Gly574Arg (1810GrA) / Gly574Arg (1810GrA) 135 (Columbian/white) Trp536X (1698GrA) / Trp536X (1698GrA) 175 (French) 1798_1800delTTC / Arg405His (1304GrA) 20 (Finnish) Trp361X (1173GrA) / Trp361X (1173GrA) 154 (Finnish) Trp361X (1173GrA) / … 116 (Norwegian) Trp361X (1173GrA) / Trp361X (1173GrA) 163 (Swedish) Trp361X (1173GrA) / Leu572Pro (1805TrC) 15 (U.S./white) 1568_1572delTCTTT / IVS1 -2 ArG 143 (SA/Asian) Arg164X (580CrT) / Arg121X (451CrT) 25 (SA/Asian) Arg243X (876CrT) / Arg243X (876CrT) 40 (Japanese) Arg419His (1396GrA) / Arg419His (1396GrA) 46 (Japanese) Arg389His (1306GrA) / Arg389His (1306GrA) 63 (Japanese) del exon 3 / del exon 3 113 (Japanese) Arg389His (1306GrA) / Arg389His (1306GrA) 132 (Japanese) Arg419His (1396GrC) / Arg550Ser (1790ArC) 140 (Japanese) Arg408X (1362CrT) / Arg408X (1362CrT) 146 (Japanese) Arg389His (1306GrA) / Arg389His (1306GrA) 157 (U.S./white) Arg419Pro (1396GrC) / Arg419Pro (1396GrC) 149 (African American) Glu146Gln (576GrC) / … 1c,e (German/Swiss) Trp361X / Trp361X 2c,e (U.S./Amish) Gly574Arg / Gly574Arg 3c,e (U.S./white) Trp361X / Tyr658X 5c,d (U.S./white) Trp361X / Arg412X 6c,e (U.S./white) Leu596Arg / … 7d (U.S./Hispanic) Arg412X / del547Cr191X 8c,e (New Zealand/white) Trp361X / … 4e (Chinese) Arg263Gln / Pro231Thr 9e (Chinese) Arg408X / … a GenBank accession number AF312715. Login to comment
146 of Alleles Frequency Restriction-Enzyme Recognition ABCG5: Glu146Gln 1 .05 Gain of AlwNI Arg243X 2 .10 Gain of AlwNI Arg389His 6 .30 Loss of BstUI Arg408X 3 .15 Loss of AvaI Arg419Pro 2 .10 Loss of BstUI Arg419His 3 .15 Loss of BstUI del exon 3 2 .10 … Arg550Ser 1 .05 … Total 20 ABCG8: Arg121X 3 .061 Gain of DdeI Arg164stop 1 .020 … Gln172X 1 .020 Gain of BfaI Arg184His 1 .020 Gain of NalIII Pro231Thr 1 .020 Loss of NlaIV Arg263Gln 1 .020 Gain of AluI Trp361X 19 .39 … Arg405His 1 .020 … Arg412X 3 .061 Gain of DdeI Leu501Pro 1 .020 Loss of AluI Trp536X 2 .041 Gain of AhdI Arg543Ser 1 .020 … Leu572Pro 1 .020 Gain of FauI Gly574Glu 1 .020 Loss of MspI Gly574Arg 4 .082 Loss of MspI Leu596Arg 1 .020 Gain of MspI Tyr658X 2 .041 Gain of SfcI IVS1 -2ArG 3 .061 Gain of BtgI 1798_1800delTTC 1 .020 … 1568_1572delTCTTT 1 .020 … Total 49 Mutations of Sterolin-2/ABCG8 as the Cause of Sitosterolemia Information on the exon/intron boundaries was used to screen probands, including those known to be mutated for sterolin-1, and to compare them to normal controls. Login to comment
154 Table 3 shows a compilation of the frequency of each mutation identified thus far. Surprisingly, Trp361X is the most common mutation in sterolin-2, and Arg389His is the most common mutation in sterolin-1. Login to comment
182 Two mutations-Arg389His in ABCG5 and Trp361X in ABCG8-are very common. Login to comment
183 Arg389His is found only in the Japanese population, although we did not detect this mutation a random sample of 82 Japanese subjects. Login to comment
184 Arg389His is found only in the Japanese population, although we did not detect this mutation a random sample of 82 Japanese subjects. Login to comment
155 Surprisingly, Trp361X is the most common mutation in sterolin-2, and Arg389His is the most common mutation in sterolin-1. Login to comment
185 Arg389His is found only in the Japanese population, although we did not detect this mutation a random sample of 82 Japanese subjects. Login to comment