ABCB11 p.Arg1231Trp
| Reviews: |
p.Arg1231Gln
D
p.Arg1231Trp D |
| Predicted by SNAP2: | A: D (91%), C: D (91%), D: D (95%), E: D (95%), F: D (95%), G: D (91%), H: D (91%), I: D (91%), K: D (91%), L: D (91%), M: D (91%), N: D (91%), P: D (95%), Q: D (91%), S: D (91%), T: D (91%), V: D (91%), W: D (95%), Y: D (95%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Hepatocellular carcinoma in ten children under fiv... Hepatology. 2006 Aug;44(2):478-86. Knisely AS, Strautnieks SS, Meier Y, Stieger B, Byrne JA, Portmann BC, Bull LN, Pawlikowska L, Bilezikci B, Ozcay F, Laszlo A, Tiszlavicz L, Moore L, Raftos J, Arnell H, Fischler B, Nemeth A, Papadogiannakis N, Cielecka-Kuszyk J, Jankowska I, Pawlowska J, Melin-Aldana H, Emerick KM, Whitington PF, Mieli-Vergani G, Thompson RJ
Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency.
Hepatology. 2006 Aug;44(2):478-86., [PMID:16871584]
Abstract [show]
Hepatocellular carcinoma (HCC) is rare in young children. We attempted to see if immunohistochemical and mutational-analysis studies could demonstrate that deficiency of the canalicular bile acid transporter bile salt export pump (BSEP) and mutation in ABCB11, encoding BSEP, underlay progressive familial intrahepatic cholestasis (PFIC)--or "neonatal hepatitis" suggesting PFIC--that was associated with HCC in young children. We studied 11 cases of pediatric HCC in the setting of PFIC or "neonatal hepatitis" suggesting PFIC. Archival liver were retrieved and immunostained for BSEP. Mutational analysis of ABCB11 was performed in leukocyte DNA from available patients and parents. Among the 11 nonrelated children studied aged 13-52 months at diagnosis of HCC, 9 (and a full sibling, with neonatal hepatitis suggesting PFIC, of a tenth from whom liver was not available) had immunohistochemical evidence of BSEP deficiency; the eleventh child did not. Mutations in ABCB11 were demonstrated in all patients with BSEP deficiency in whom leukocyte DNA could be studied (n = 7). These mutations were confirmed in the parents (n = 14). With respect to the other 3 children with BSEP deficiency, mutations in ABCB11 were demonstrated in all 5 parents in whom leukocyte DNA could be studied. Thirteen different mutations were found. In conclusion, PFIC associated with BSEP deficiency represents a previously unrecognized risk for HCC in young children. Immunohistochemical evidence of BSEP deficiency correlates well with demonstrable mutation in ABCB11.
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No. Sentence Comment
177 Among the missense changes is 1 in exon 27 (patient C); those in patients D, E, and H (890AϾG [E297G], exon 9) and the other mutation in patient C (1445AϾG [D482G], exon 14) have been described previously.8 The 890AϾG (E297G) and 1445AϾG (D482G) mutations reportedly affect BSEP transport activity,21,33 with altered trafficking of BSEP to the canalicular membrane.33-35 The mutation in patient C, 3691CϾT (R1231W), is predicted to alter an amino acid residue between the ATP-binding cassette signature motif and the Walker B motif of BSEP.
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ABCB11 p.Arg1231Trp 16871584:177:437
status: NEW[hide] Missense mutations and single nucleotide polymorph... Hepatology. 2009 Feb;49(2):553-67. Byrne JA, Strautnieks SS, Ihrke G, Pagani F, Knisely AS, Linton KJ, Mieli-Vergani G, Thompson RJ
Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing.
Hepatology. 2009 Feb;49(2):553-67., [PMID:19101985]
Abstract [show]
The gene encoding the human bile salt export pump (BSEP), ABCB11, is mutated in several forms of intrahepatic cholestasis. Here we classified the majority (63) of known ABCB11 missense mutations and 21 single-nucleotide polymorphisms (SNPs) to determine whether they caused abnormal ABCB11 pre-messenger RNA splicing, abnormal processing of BSEP protein, or alterations in BSEP protein function. Using an in vitro minigene system to analyze splicing events, we found reduced wild-type splicing for 20 mutations/SNPs, with normal mRNA levels reduced to 5% or less in eight cases. The common ABCB11 missense mutation encoding D482G enhanced aberrant splicing, whereas the common SNP A1028A promoted exon skipping. Addition of exogenous splicing factors modulated several splicing defects. Of the mutants expressed in vitro in CHO-K1 cells, most appeared to be retained in the endoplasmic reticulum and degraded. A minority had BSEP levels similar to wild-type. The SNP variant A444 had reduced levels of protein compared with V444. Treatment with glycerol and incubation at reduced temperature overcame processing defects for several mutants, including E297G. Taurocholate transport by two assessed mutants, N490D and A570T, was reduced compared with wild-type. Conclusion: This work is a comprehensive analysis of 80% of ABCB11 missense mutations and single-nucleotide polymorphisms at pre-mRNA splicing and protein processing/functional levels. We show that aberrant pre-mRNA splicing occurs in a considerable number of cases, leading to reduced levels of normal mRNA. Thus, primary defects at either the protein or the mRNA level (or both) contribute significantly to BSEP deficiency. These results will help to develop mutation-specific therapies for children and adults suffering from intrahepatic cholestasis due to BSEP deficiency.
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89 To varying degrees, exon skipping was also seen for the nucleotide changes associated with other missense mutations: T463I (c.1388CϾT; 90% wild-type splicing; Fig. 2C), A926P (c.2776GϾC; 90%; Fig. 2E), A1110E (c.3329CϾA; 90%), G1116R (c.3346GϾC; 80%), R1128C (c.3382CϾT; 85%), R1128H (c.3383GϾA; 90%), and R1231W (c.3691CϾT; 5%; Fig. 2F).
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ABCB11 p.Arg1231Trp 19101985:89:342
status: NEW127 None of the factors altered the splicing of A167V (c.500CϾT; Fig. 4A), or R1231W (c.3691CϾT; Fig. 4C).
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ABCB11 p.Arg1231Trp 19101985:127:80
status: NEW[hide] ATP8B1 and ABCB11 analysis in 62 children with nor... Hepatology. 2010 May;51(5):1645-55. Davit-Spraul A, Fabre M, Branchereau S, Baussan C, Gonzales E, Stieger B, Bernard O, Jacquemin E
ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history.
Hepatology. 2010 May;51(5):1645-55., [PMID:20232290]
Abstract [show]
Progressive familial intrahepatic cholestasis (PFIC) types 1 and 2 are characterized by normal serum gamma-glutamyl transferase (GGT) activity and are due to mutations in ATP8B1 (encoding FIC1) and ABCB11 (encoding bile salt export pump [BSEP]), respectively. Our goal was to evaluate the features that may distinguish PFIC1 from PFIC2 and ease their diagnosis. We retrospectively reviewed charts of 62 children with normal-GGT PFIC in whom a search for ATP8B1 and/or ABCB11 mutation, liver BSEP immunostaining, and/or bile analysis were performed. Based on genetic testing, 13 patients were PFIC1 and 39 PFIC2. The PFIC origin remained unknown in 10 cases. PFIC2 patients had a higher tendency to develop neonatal cholestasis. High serum alanine aminotransferase and alphafetoprotein levels, severe lobular lesions with giant hepatocytes, early liver failure, cholelithiasis, hepatocellular carcinoma, very low biliary bile acid concentration, and negative BSEP canalicular staining suggest PFIC2, whereas an absence of these signs and/or presence of extrahepatic manifestations suggest PFIC1. The PFIC1 and PFIC2 phenotypes were not clearly correlated with mutation types, but we found tendencies for a better prognosis and response to ursodeoxycholic acid (UDCA) or biliary diversion (BD) in a few children with missense mutations. Combination of UDCA, BD, and liver transplantation allowed 87% of normal-GGT PFIC patients to be alive at a median age of 10.5 years (1-36), half of them without liver transplantation. CONCLUSION: PFIC1 and PFIC2 differ clinically, biochemically, and histologically at presentation and/or during the disease course. A small proportion of normal-GGT PFIC is likely not due to ATP8B1 or ABCB11 mutations.
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101 11† p.R1128C p.R1128C na na PFIC2 no.
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ABCB11 p.Arg1231Trp 20232290:101:117
status: NEW104 14b† p.I420T p.I1061VfsX34 na na PFIC2 no. 15*,‡ p.A167T p.G1058HfsX38 0.5 BSEP À PFIC2 no. 16* p.R1231W p.I528X na na PFIC2 no. 17 p.M62K p.I112T þ p.R698H 0.10 BSEP À PFIC2 no. 18* p.E297G p.H484RfsX5 0.16 BSEP À PFIC2 no. 19* p.E297G p.I610GfsX45 0.23 BSEP À PFIC2 no.
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ABCB11 p.Arg1231Trp 20232290:104:117
status: NEW[hide] Severe bile salt export pump deficiency: 82 differ... Gastroenterology. 2008 Apr;134(4):1203-14. doi: 10.1053/j.gastro.2008.01.038. Epub 2008 Jan 18. Strautnieks SS, Byrne JA, Pawlikowska L, Cebecauerova D, Rayner A, Dutton L, Meier Y, Antoniou A, Stieger B, Arnell H, Ozcay F, Al-Hussaini HF, Bassas AF, Verkade HJ, Fischler B, Nemeth A, Kotalova R, Shneider BL, Cielecka-Kuszyk J, McClean P, Whitington PF, Sokal E, Jirsa M, Wali SH, Jankowska I, Pawlowska J, Mieli-Vergani G, Knisely AS, Bull LN, Thompson RJ
Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families.
Gastroenterology. 2008 Apr;134(4):1203-14. doi: 10.1053/j.gastro.2008.01.038. Epub 2008 Jan 18., [PMID:18395098]
Abstract [show]
BACKGROUND & AIMS: Patients with severe bile salt export pump (BSEP) deficiency present as infants with progressive cholestatic liver disease. We characterized mutations of ABCB11 (encoding BSEP) in such patients and correlated genotypes with residual protein detection and risk of malignancy. METHODS: Patients with intrahepatic cholestasis suggestive of BSEP deficiency were investigated by single-strand conformation polymorphism analysis and sequencing of ABCB11. Genotypes sorted by likely phenotypic severity were correlated with data on BSEP immunohistochemistry and clinical outcome. RESULTS: Eighty-two different mutations (52 novel) were identified in 109 families (9 nonsense mutations, 10 small insertions and deletions, 15 splice-site changes, 3 whole-gene deletions, 45 missense changes). In 7 families, only a single heterozygous mutation was identified despite complete sequence analysis. Thirty-two percent of mutations occurred in >1 family, with E297G and/or D482G present in 58% of European families (52/89). On immunohistochemical analysis (88 patients), 93% had abnormal or absent BSEP staining. Expression varied most for E297G and D482G, with some BSEP detected in 45% of patients (19/42) with these mutations. Hepatocellular carcinoma or cholangiocarcinoma developed in 15% of patients (19/128). Two protein-truncating mutations conferred particular risk; 38% (8/21) of such patients developed malignancy versus 10% (11/107) with potentially less severe genotypes (relative risk, 3.7 [confidence limits, 1.7-8.1; P = .003]). CONCLUSIONS: With this study, >100 ABCB11 mutations are now identified. Immunohistochemically detectable BSEP is typically absent, or much reduced, in severe disease. BSEP deficiency confers risk of hepatobiliary malignancy. Close surveillance of BSEP-deficient patients retaining their native liver, particularly those carrying 2 null mutations, is essential.
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150 Missense Mutations in ABCB11 Nucleotide change Predicted effect Exon CpG site Location Change in: Size Charge Hyd/Pol Shape c.149Tb0e;C p.Leu50Ser 4 No NH2 term Y Y Y c.470Ab0e;G p.Tyr157Cys 6 No TM2 Y Y Y c.725Cb0e;T p.Thr242Ile 8 No TM4 Y Y c.890Ab0e;G p.Glu297Gly 9 No IC2 Y Y Y c.908Gb0e;A p.Arg303Lys 9 No IC2 c.937Cb0e;A p.Arg313Ser 10 Yes IC2 Y Y Y Y c.980Gb0e;A p.Gly327Glu 10 No TM5 Y Y Y c.1168Gb0e;C p.Ala390Pro 11 No TM/NBF Y c.1229Gb0e;A p.Gly410Asp 12 No TM/NBF Y Y c.1238Tb0e;G p.Leu413Trp 12 No TM/NBF c.1388Cb0e;T p.Thr463Ile 13 No Adj Walker A Y Y Y c.1396Cb0e;A p.Gln466Lys 13 No Adj Walker A Y c.1409Gb0e;A p.Arg470Gln 13 Yes Adj Walker A Y c.1415Ab0e;G p.Tyr472Cys 13 No Adj Walker A Y Y Y c.1442Tb0e;A p.Val481Glu 14 No NBF1 Y Y Y c.1445Ab0e;G p.Asp482Gly 14 No NBF1 Y Y c.1460Gb0e;C p.Arg487Pro 14 Yes NBF1 Y Y Y Y c.1468Ab0e;G p.Asn490Asp 14 No NBF1 Y c.1535Tb0e;C p.Ile512Thr 14 No NBF1 Y Y Y c.1544Ab0e;C p.Asn515Thr 14 No NBF1 Y Y c.1550Gb0e;A p.Arg517His 14 Yes NBF1 Y Y c.1621Ab0e;C p.Ile541Leu 14 No NBF1 c.1622Tb0e;C p.Ile541Thr 14 No NBF1 Y Y Y c.1643Tb0e;A p.Phe548Tyr 15 No Adj ABC c.1685Gb0e;A p.Gly562Asp 15 No ABC Y Y c.1708Gb0e;A p.Ala570Thr 15 Yes ABC/Walker B Y c.1763Cb0e;T p.Ala588Val 15 No Adj Walker B Y c.2272Gb0e;C p.Gly758Arg 19 No NBF/TM Y Y Y c.2296Gb0e;A p.Gly766Arg 19 Yes TM7 Y Y Y c.2494Cb0e;T p.Arg832Cys 21 Yes IC3 Y Y Y Y c.2576Cb0e;G p.Thr859Arg 21 No IC3 Y Y Y Y c.2842Cb0e;T p.Arg948Cys 23 Yes IC4 Y Y Y Y c.2935Ab0e;G p.Asn979Asp 23 No TM11 Y c.2944Gb0e;A p.Gly982Arg 23 Yes TM11 Y Y Y c.3086Cb0e;A p.Thr1029Lys 24 No TM12 Y Y Y Y c.3329Cb0e;A p.Ala1110Glu 25 Yes Adj Walker A Y Y Y c.3382Cb0e;T p.Arg1128Cys 25 Yes Adj Walker A Y Y Y Y c.3457Cb0e;T p.Arg1153Cys 26 Yes NBF2 Y Y Y Y c.3458Gb0e;A p.Arg1153His 26 Yes NBF2 Y Y c.3460Tb0e;C p.Ser1154Pro 26 No NBF2 Y c.3628Ab0e;C p.Thr1210Pro 27 No Adj ABC Y c.3691Cb0e;T p.Arg1231Trp 27 Yes ABC/Walker B Y Y c.3692Gb0e;A p.Arg1231Gln 27 Yes ABC/Walker B Y c.3724Cb0e;A p.Leu1242Ile 27 No Walker B c.3892Gb0e;A p.Gly1298Arg 28 No NBF2 Y Y Y NOTE.
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ABCB11 p.Arg1231Trp 18395098:150:2007
status: NEW[hide] Genetic variations of bile salt transporters. Drug Discov Today Technol. 2014 Jun;12:e55-67. doi: 10.1016/j.ddtec.2014.03.006. Kubitz R, Droge C, Kluge S, Stindt J, Haussinger D
Genetic variations of bile salt transporters.
Drug Discov Today Technol. 2014 Jun;12:e55-67. doi: 10.1016/j.ddtec.2014.03.006., [PMID:25027376]
Abstract [show]
Bile salt transporters directly or indirectly influence biological processes through physicochemical or signalling properties of bile salts. The coordinated action of uptake and efflux transporters in polarized epithelial cells of the liver, biliary tree, small intestine and kidney determine bile salt concentrations in different compartments of the body. Genetic variations of bile salt transporters lead to clinical relevant phenotypes of varying severity ranging from a predisposition for drug-induced liver injury to rapidly progressing end-stage liver disease. This review focuses on the impact of genetic variations of bile salt transporters including BSEP, NTCP, ASBT and OSTalpha/beta and discusses approaches for transporter analysis.
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No. Sentence Comment
137 BSEP/Bsep NTCP ASBT Exon skipping E186G G1116R G319G R1128C T463I R1128H A926P E1186K A1028Aa R1231W A1110E Aberrant splicing E297K R1153H R832C S1154P S1144R No splice product T586I R1231Q Reduced plasma membrane expression E135K A570T I223T E297Gb N591Sb V444A R1050C Intracellular retention Y818F G982R Reduced or absent bile salt transport A570T R432T A64T K314E V98Ic M264V I206V Q558H I223T C144Y P290S E297Gb N591Sb S267F L243P G374S E1186K I279T T262M a A1028A induces significant exon skipping in vitro but probably not in vivo (unpublished data; Dro &#a8;ge, Ha &#a8;ussinger, Kubitz).
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ABCB11 p.Arg1231Trp 25027376:137:94
status: NEW[hide] Hypothyroidism Associated with ATP8B1 Deficiency. J Pediatr. 2015 Dec;167(6):1334-1339.e1. doi: 10.1016/j.jpeds.2015.08.037. Epub 2015 Sep 15. Li L, Deheragoda M, Lu Y, Gong J, Wang J
Hypothyroidism Associated with ATP8B1 Deficiency.
J Pediatr. 2015 Dec;167(6):1334-1339.e1. doi: 10.1016/j.jpeds.2015.08.037. Epub 2015 Sep 15., [PMID:26382629]
Abstract [show]
OBJECTIVE: To examine whether hypothyroidism is an extrahepatic feature of ATPase, aminophospholipid transporter, class I, type 8B, member 1 (ATP8B1) deficiency. STUDY DESIGN: Children with normal gamma-glutamyltransferase cholestasis (n = 47; 13 patients with ATP8B1 deficiency, 19 with ATP-binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11) deficiency, and 15 without either ATP8B1 or ABCB11 mutations) were enrolled. Clinical information and thyroid function test results were retrospectively retrieved from clinical records and compared. Hypothyroidism was diagnosed by clinical-biochemistry criteria (thyroid function test results). RESULTS: Three out of 13 patients with ATP8B1 deficiency were diagnosed as hypothyroid and 2 as subclinically hypothyroid. The frequency of hypothyroidism and subclinical hypothyroidism was significantly higher than in patients with ABCB11 deficiency (5/13 vs 0/19, P = .006) and in patients without ATP8B1 or ABCB11 mutations (5/13 vs 0/15, P = .013). Thyroid function test results normalized after hormone replacement in all 5 patients, with no relief of cholestasis. CONCLUSIONS: As hypothyroidism can be another extrahepatic feature of ATP8B1 deficiency, thyroid function should be monitored in these patients.
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71 ABCB11 mutations and immunostaining in patients with ABCB11 mutations Patient ID Sex Nucleotide change Amino acid change Mutation origin BSEP expression GGT expression 244 Female c.145C>T/- p.Q49X/- Paternal/- Absent Normal 653 Female c.1197+1G>T/c.1197+1G>T -/- Paternal/maternal Not assessed Not assessed 727 Male c.2782C>T/c.3593A>G p.R928X/p.H1198R Maternal/paternal Not assessed Not assessed 889 Female c.3457C>T/c.3623A>G p.R1153C/p.Y1208C Paternal/maternal Absent Normal 919 Female c.1493T>C/c.1493T>C p.I498T/p.I498T Paternal/maternal Not assessed Not assessed 996 Male c.612-2_4 CTA>TT/- -/- Maternal/- Absent Normal 1022 Male c.212T>A/c.677C>T p.L71H/p.S226L Paternal/maternal Absent Normal 1131 Male c.409G>A/c.2216delC p.E137K/p.P740QfsX6 De novo/paternal Absent Normal 1134 Male c.1760C>G/c.3677G>C p.S587X/p.R1226P Maternal/paternal Absent Absent 1139 Female c.2935A>G/c.3746T>G p.N979D/p.L1249X Not assessed Not assessed Not assessed 1140 Male c.542G>T/c.1370_1372dupGTG p.R181I/p.V458dup Maternal/paternal Not assessed Not assessed 1219 Female c.872T>C/c.3691C>T p.V291A/p.R1231W Maternal/paternal Not assessed Not assessed 334* Female c.2944G>A/- p.G982R/- Not assessed Normal Normal 802* Female c.3458G>A/- p.R1153H/- Not assessed Not assessed Not assessed 862* Male c.634G>A/c.849A>C/c.1638G>T p.A212T/p.E283D/p.Q546H Maternal/maternal/de novo Not assessed Not assessed 864* Male c.1727A>G/- p.N576S/- Paternal/- Normal Normal 1165* Male c.1583T>C/c.1583T>C p.I528T/p.I528T Not assessed Not assessed Not assessed 1167* Male c.334A>G/c.3233T>C p.I112V/p.I1078T Not assessed Not assessed Not assessed 1242* Male c.2783G>A/- p.R928Q/- Not assessed Not assessed Not assessed Bold: Novel mutation.
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ABCB11 p.Arg1231Trp 26382629:71:1089
status: NEW