ABCG5 p.Arg243*
| ClinVar: |
c.727C>T
,
p.Arg243*
D
, Pathogenic
|
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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).
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ABCG5 p.Arg243* 11138003:29:36
status: NEW35 Mutations resulting in R243X, R408X, R389H and R419H/P altered cleavage sites of restriction enzymes.
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ABCG5 p.Arg243* 11138003:35:23
status: NEW36 R243X mutation segregated with disease in pedigree 500; both parents are carriers and both affected children are homozygous (Fig. 2a) for the mutation.
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ABCG5 p.Arg243* 11138003:36:0
status: NEW46 Mutation R243X (left-hand panels) results in a gain of the AlwnI site.
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ABCG5 p.Arg243* 11138003:46:9
status: NEW62 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.
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ABCG5 p.Arg243* 11138003:62:1819
status: NEWX
ABCG5 p.Arg243* 11138003:62:2207
status: NEW[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.
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ABCG5 p.Arg243* 12124998:77:185
status: VERIFIED[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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No. Sentence Comment
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.
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ABCG5 p.Arg243* 12359125:112:347
status: NEW