ABCMdb

ABCG8 p.Trp361*

ClinVar:

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[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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No. Sentence Comment
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] Stomatocytic haemolysis and macrothrombocytopenia ... Br J Haematol. 2005 Jul;130(2):297-309. Rees DC, Iolascon A, Carella M, O'marcaigh AS, Kendra JR, Jowitt SN, Wales JK, Vora A, Makris M, Manning N, Nicolaou A, Fisher J, Mann A, Machin SJ, Clayton PT, Gasparini P, Stewart GW
Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia.
Br J Haematol. 2005 Jul;130(2):297-309., [PMID:16029460]

Abstract [show]
Phytosterolaemia (sitosterolaemia) is a recessively inherited metabolic condition in which the absorption of both cholesterol and plant-derived cholesterol-like molecules at the gut is unselective and unrestricted. In haematology, Mediterranean stomatocytosis or Mediterranean macrothrombocytopenia is a poorly understood haematological condition that combines stomatocytic haemolysis with the presence of very large platelets. Five pedigrees showing this haematology were identified. Gas chromatography mass spectrometry (GC-MS) showed that all of the patients with this highly specific haematology had grossly elevated levels of phytosterols in the blood, diagnostic of phytosterolaemia. All showed mutations in the ABCG5 and ABCG8 previously linked to phytosterolaemia. Three pedigrees showed five new mutations, while two pedigrees showed the common W361X mutation in ABCG8. We draw the following four conclusions: (i) that Mediterranean stomatocytosis/macrothrombocytopenia is caused by an excess of phytosterols in the blood; (ii) that phytosterolaemia, which does not respond to standard statin treatment, can be diagnosed via the distinctive haematology described here, even when the cholesterol is normal; (iii) that phytosterolaemia should be considered in the differential diagnosis of all patients with large platelets; and (iv) that the platelet size should be noted in patients with hypercholesterolaemia.

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174 Family Sitosterol level (lmol/l) ABCG5 ABCG8 A E77X (229G>T) A-I-2 44 m/n A-II-1 1471 m/m A-II-2 17 n/n A-II-3 57 n/n A-II-4 970 m/m A-II-5 625 m/m A-II-9 508 m/m B IVS11+3insT R50C (148C>T) E146X (436G>T), M622V (1864A>G) B-I-1 77 n/n m/n B-I-2 42 m/n n/n B-II-1 2230 m/n m/n B-II-2 2350 m/n m/n B-II-3 137 n/n m/n C Q604E (1810C>G) Q271X (811C>T) IV9-3insT IV8-1G/A C54Y (161G>A) C-I-1 114 m/n n/n m/n m/n C-I-2 29 m/m m/n n/n m/m C-II-1 2100 m/n m/n m/n m/n C-II-2 2580 m/n m/n m/n m/n D W361X (1083G>A) D-I-1 22 m/n D-II-1 715 m/m E W361X (1083G>A) E-I-1 23 m/n E-II-1 1844 m/m E-II-2 21 n/n Mutations are shown in bold and large font. Login to comment
8 Three pedigrees showed five new mutations, while two pedigrees showed the common W361X mutation in ABCG8. Login to comment
131 Affected siblings in family C were compound heterozygous for Q271X and IV8-1G>A, which are both novel, while both affected individuals in families D and E were homozygous for the previously described W361X mutation in ABCG8, which is the single commonest mutation in phytosterolaemia (Berge et al, 2000; Lee et al, 2001b; Lu et al, 2001). Login to comment

[hide] A detailed Hapmap of the Sitosterolemia locus span... BMC Med Genet. 2006 Feb 28;7:13. Pandit B, Ahn GS, Hazard SE, Gordon D, Patel SB
A detailed Hapmap of the Sitosterolemia locus spanning 69 kb; differences between Caucasians and African-Americans.
BMC Med Genet. 2006 Feb 28;7:13., [PMID:16507104]

Abstract [show]
BACKGROUND: Sitosterolemia is an autosomal recessive disorder that maps to the sitosterolemia locus, STSL, on human chromosome 2p21. Two genes, ABCG5 and ABCG8, comprise the STSL and mutations in either cause sitosterolemia. ABCG5 and ABCG8 are thought to have evolved by gene duplication event and are arranged in a head-to-head configuration. We report here a detailed characterization of the STSL in Caucasian and African-American cohorts. METHODS: Caucasian and African-American DNA samples were genotypes for polymorphisms at the STSL locus and haplotype structures determined for this locus RESULTS: In the Caucasian population, 13 variant single nucleotide polymorphisms (SNPs) were identified and resulting in 24 different haplotypes, compared to 11 SNPs in African-Americans resulting in 40 haplotypes. Three polymorphisms in ABCG8 were unique to the Caucasian population (E238L, INT10-50 and G575R), whereas one variant (A259V) was unique to the African-American population. Allele frequencies of SNPs varied also between these populations. CONCLUSION: We confirmed that despite their close proximity to each other, significantly more variations are present in ABCG8 compared to ABCG5. Pairwise D' values showed wide ranges of variation, indicating some of the SNPs were in strong linkage disequilibrium (LD) and some were not. LD was more prevalent in Caucasians than in African-Americans, as would be expected. These data will be useful in analyzing the proposed role of STSL in processes ranging from responsiveness to cholesterol-lowering drugs to selective sterol absorption.

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No. Sentence Comment
49 We selected 12 parents (24 chromosomes) carrying the commonest mutation, W361X, and where complete genotype information was available to compute recombination frequencies. Login to comment
122 Age of mutation was calculated considering W361X as the most common disease causing mutation. Login to comment
130 This SNP was also closely spaced to W361X mutation. Login to comment

[hide] A genome-wide association scan identifies the hepa... Nat Genet. 2007 Aug;39(8):995-9. Epub 2007 Jul 15. Buch S, Schafmayer C, Volzke H, Becker C, Franke A, von Eller-Eberstein H, Kluck C, Bassmann I, Brosch M, Lammert F, Miquel JF, Nervi F, Wittig M, Rosskopf D, Timm B, Holl C, Seeger M, ElSharawy A, Lu T, Egberts J, Fandrich F, Folsch UR, Krawczak M, Schreiber S, Nurnberg P, Tepel J, Hampe J
A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease.
Nat Genet. 2007 Aug;39(8):995-9. Epub 2007 Jul 15., [PMID:17632509]

Abstract [show]
With an overall prevalence of 10-20%, gallstone disease (cholelithiasis) represents one of the most frequent and economically relevant health problems of industrialized countries. We performed an association scan of >500,000 SNPs in 280 individuals with gallstones and 360 controls. A follow-up study of the 235 most significant SNPs in 1,105 affected individuals and 873 controls replicated the disease association of SNP A-1791411 in ABCG8 (allelic P value P(CCA) = 4.1 x 10(-9)), which was subsequently attributed to coding variant rs11887534 (D19H). Additional replication was achieved in 728 German (P = 2.8 x 10(-7)) and 167 Chilean subjects (P = 0.02). The overall odds ratio for D19H carriership was 2.2 (95% confidence interval: 1.8-2.6, P = 1.4 x 10(-14)) in the full German sample. Association was stronger in subjects with cholesterol gallstones (odds ratio = 3.3), suggesting that His19 might be associated with a more efficient transport of cholesterol into the bile.

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No. Sentence Comment
49 For the sake of completeness, we also included two sitosterolemia SNPs: the SNP in ABCG8 responsible for premature stop R121X, which was monomorphic, and the SNP responsible for premature stop W361X in ABCG8, for which we observed one heterozygote each in panel B controls and affected individuals. 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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No. Sentence Comment
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] Liver transplantation in a patient with sitosterol... Gastroenterology. 2006 Feb;130(2):542-7. Miettinen TA, Klett EL, Gylling H, Isoniemi H, Patel SB
Liver transplantation in a patient with sitosterolemia and cirrhosis.
Gastroenterology. 2006 Feb;130(2):542-7., [PMID:16472606]

Abstract [show]
Sitosterolemia (MIM 210250) is a rare genetic disorder caused by disruption of the normal mechanisms that regulate dietary cholesterol absorption and prevent the accumulation of noncholesterol sterols. As a result of this defect, affected individuals accumulate high concentrations of plant sterols in plasma and tissues. They present clinically with tendon or tuberoeruptive xanthomas, premature coronary artery disease, and/or hemolytic anemia. Two genes, ABCG5 and ABCG8, compose the STSL locus, and complete mutation in either, but not both, results in disease. The expression of these genes is confined to the intestine and liver. They are thought to function as sterol efflux pumps. It is not clear which organ, liver or intestine, is of greater importance in maintaining sterol balance with respect to noncholesterol sterols. We report here a case of a patient who presented with "chronic active liver disease" and was found to have sitosterolemia by chance and subsequently underwent orthotopic liver transplantation. Following transplantation, the grossly elevated pretransplantation serum plant sterol levels decreased to values only slightly higher than those of the patient's heterozygous father. This case highlights 2 important features: (1) The liver functions as the predominant organ for maintaining noncholesterol sterol balance (because the intestinal defect was not altered), and (2) a new clinical feature of undiagnosed sitosterolemia may be "idiopathic" liver disease. Because the diagnosis of sitosterolemia is based on specialized plasma analyses, we would propose that some consideration to this diagnosis should be given in appropriate cases.

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No. Sentence Comment
76 Genetic analyses of DNA from the proband showed that he carried the following 2 mutations: W361X (G1173A) and E423D (G1359T) in ABCG8. Login to comment
78 Although the W361X mutation has been previously reported, the E423D has not been described and is novel.18 In more than 100 normal alleles examined, E423D was not detected. Login to comment