ABCMdb

ABCG8 p.Leu596Arg

ClinVar:	c.1787T>G , p.Leu596Arg D , Pathogenic
Predicted by SNAP2:	A: D (85%), C: D (75%), D: D (95%), E: D (95%), F: D (80%), G: D (91%), H: D (85%), I: N (57%), K: D (95%), M: N (57%), N: D (91%), P: D (95%), Q: D (85%), R: D (95%), S: D (91%), T: D (85%), V: D (53%), W: D (95%), Y: D (66%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: N, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: D,

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[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] Mutations in ATP-cassette binding proteins G5 (ABC... Hum Mutat. 2001 Oct;18(4):359-60. Hubacek JA, Berge KE, Cohen JC, Hobbs HH
Mutations in ATP-cassette binding proteins G5 (ABCG5) and G8 (ABCG8) causing sitosterolemia.
Hum Mutat. 2001 Oct;18(4):359-60., [PMID:11668628]

Abstract [show]
Sitosterolemia is an autosomal recessive disorder caused by mutations in two adjacent genes encoding coordinately regulated ATP binding cassette (ABC) half transporters (ABCG5 and ABCG8). In this paper we describe three novel mutations causing sitosterolemia: 1) a frameshift mutation (c.336-337insA) in ABCG5 that results in premature termination of the protein at amino acid 197; 2) a missense mutation that changes a conserved residue c.1311C>G; N437K) in ABCG5 and 3) a splice site mutation in ABCG8 (IVS1-2A>G). This study expands the spectrum of the ABCG5 and ABCG8 mutations that cause sitosterolemia. Nine nonsynonymous polymorphisms are also reported: I523V, C600Y, Q604E, and M622V in ABCG5; and D19H, Y54C, T400K, A632V, and Y641F in ABCG8.

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12 PATIENTS AND METHODS Patients The first patient was a Caucasian girl who was previously found to be heterozygous for a missense mutation in ABCG8 (c.1787T>G; L596R); no mutation was found in the other ABCG8 allele (Berge et al. 2000; Stell and Sprecher 1990). Login to comment

[hide] Mutations in the human ATP-binding cassette transp... Hum Mutat. 2002 Aug;20(2):151. Heimerl S, Langmann T, Moehle C, Mauerer R, Dean M, Beil FU, von Bergmann K, Schmitz G
Mutations in the human ATP-binding cassette transporters ABCG5 and ABCG8 in sitosterolemia.
Hum Mutat. 2002 Aug;20(2):151., [PMID:12124998]

Abstract [show]
Phytosterolemia or Sitosterolemia is a rare autosomal recessive disorder characterized by highly elevated plasma levels of plant sterols and cholesterol as a consequence of hyperabsorption and impaired biliary secretion of sterols. The disease is caused by mutations in two half size ATP-binding cassette transporters, ABCG5 and ABCG8. We have analyzed the genomic sequence of ABCG5 and ABCG8 in five well-characterized patients with Sitosterolemia. In the first patient we found a heterozygous mutation in exon 8 of the ABCG5 gene leading to a premature termination of the protein (Arg408Ter). This German patient is the first European showing a mutation of the ABCG5 gene. In a second patient we found a novel heterozygous mutation in exon 5 of ABCG8 (c.584T>A; Leu195Gln). Both patients were heterozygous for the identified mutation, but no mutation could be identified on the other chromosome. In three further analyzed patients we found mutations in exons 7, 9 and 11 of the ABCG8 gene, respectively, of which two result in a premature termination signal for translation products. One of these patients was compound heterozygous (Trp361Ter and Arg412Ter), the other was homozygous for Trp361Ter. The third patient was homozygous for an amino acid exchange (Gly574Arg). In conclusion this report describes one novel mutation affecting a highly conserved amino acid and two previously identified mutations in the ABCG8 gene. In addition, we identified for the first time a mutation in the ABCG5 gene of a European Sitosterolemia patient.

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77 C Y658stop R121stop R164stop Q172stop R184H L195Q P231T G574R G574E L572P L596R N ABC B S AA R263Q E146Q R405H R543S W536stop R412stop W361stop C R419P R419H R408stop R398H N437K R550S R243stop N ABCG5 ABCG8 S B A IVS1 -2A>G Del547C>191stop L501P L596R 1568_1572delTCTTT 1798_1800delTTC Del Exon 3 C336-337insA 201 * Signature 250 ABCG1 Q..EKDEG.R REMVKEILTA L GLLSCANTR TGS.... .LS GGQR KRLAIA ABCG2 ATTMTNHE.K NERINRVIEE L GLDKVADSK VGTQFIR GVS GGER KRTSIG ABCG4 S..EKQEV.K KELVTEILTA L GLMSCSHTR TAL.... .LS GGQR KRLAIA ABCG5 R..RGNPGSF QKKVEAVMAE L SLSHVADRL IGNYSLG GIS TGER RRVSIA ABCG8 PRTFSQAQ.R DKRVEDVIAE L RLRQCADTR VGNMYVR GLS GGER RRVSIG Figure 2: Alignment of the human ABC transporters G1, G2, G4, G5 and G8. The amino acid change Leu195Gln in ABCG8 found in patient 2 is located intracellularly between the Walker A and the Signature C-motif. 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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198 Three exceptions, L596R, G574E, and G574R in G8, result in the substitution of charged for neutral amino acids. Login to comment
219 Only those mutant forms of G8 that were trafficking-competent (R543S and G574R) and to a lesser extent L596R were detected in the position of the dimer. Login to comment
197 Three exceptions, L596R, G574E, and G574R in G8, result in the substitution of charged for neutral amino acids. Login to comment
218 Only those mutant forms of G8 that were trafficking-competent (R543S and G574R) and to a lesser extent L596R were detected in the position of the dimer. 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] SHRSP/Izm and WKY/NCrlCrlj rats having a missense ... Biosci Biotechnol Biochem. 2012;76(4):660-4. Epub 2012 Apr 7. Kato M, Ito Y, Tanaka Y, Sato M, Imaizumi K, Inoue N, Ikeda I
SHRSP/Izm and WKY/NCrlCrlj rats having a missense mutation in Abcg5 deposited plant sterols in the body, but did not change their biliary secretion and lymphatic absorption-comparison with Jcl:Wistar and WKY/Izm rats.
Biosci Biotechnol Biochem. 2012;76(4):660-4. Epub 2012 Apr 7., [PMID:22484926]

Abstract [show]
We had previously found plant sterols deposited in the bodies of stroke-prone spontaneously hypertensive rats (SHRSP)/Sea and Wistar Kyoto (WKY)/NCrlCrlj rats that had a missense mutation in the Abcg5 cDNA sequence that coded for ATP-binding cassette transporter (ABC) G5. We used SHRSP/Izm, WKY/NCrlCrlj, and WKY/Izm rats in the present study to determine the mechanisms for plant sterol deposition in the body. Jcl:Wistar rats were used as a control strain. A diet containing 0.5% plant sterols fed to the rats resulted in plant sterol deposition in the body of SHRSP/Izm, but not in WKY/Izm or Jcl:Wistar rats. Only a single non-synonymous nucleotide change, G1747T, resulting in a conservative cysteine substitution for glycine at amino acid 583 (Gly583Cys) in Abcg5 cDNA was identified in the SHRSP/Izm and WKY/NCrlCrlj rats. However, this mutation was not found in the WKY/Izm or Jcl:Wistar rats. No significant difference in the biliary secretion or lymphatic absorption of plant sterols was apparent between the rat strains with or without the missense mutation in Abcg5 cDNA. Our observations suggest that plant sterol deposition in rat strains with the missense mutation in Abcg5 cDNA can occur, despite there being no significant change in the biliary secretion or lymphatic absorption of plant sterols.

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104 A mutation at Leu596Arg in ABCG8 has been reported in a sitosterolemic patient,4) and it has been found that ABCG8 had a similar conformation to that of ABCG5.4) It is therefore thought that the Leu596Arg mutation in ABCG8 inhabited a region similar to the Gly583Cys mutation in ABCG5.4) The results suggest a possibility that the Gly583Cys mutation in ABCG5 influences the function of ABCG5/ ABCG8. Login to comment
106 A mutation at Leu596Arg in ABCG8 has been reported in a sitosterolemic patient,4) and it has been found that ABCG8 had a similar conformation to that of ABCG5.4) It is therefore thought that the Leu596Arg mutation in ABCG8 inhabited a region similar to the Gly583Cys mutation in ABCG5.4) The results suggest a possibility that the Gly583Cys mutation in ABCG5 influences the function of ABCG5/ ABCG8. 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