ABCMdb

PMID: 18395098

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., [PubMed]

Sentences

No. Mutations Sentence Comment

7 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly Thirty-two percent of mutations occurred in >1 family, with E297G and/or D482G present in 58% of European families (52/89). Login to comment 9 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly Expression varied most for E297G and D482G, with some BSEP detected in 45% of patients (19/42) with these mutations. Login to comment 77 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly ABCB11 p.Arg1153Cys ABCB11 p.Gly982Arg ABCB11 p.Arg575* ABCB11 p.Arg1153His The common mutations E297G, D482G, R575X, R1153C, and R1153H abolish HphI, FokI, FokI, BsrBI, and BsrBI sites, respectively, while G982R creates an AlwNI site. Login to comment 98 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly Most frequent were E297G and D482G, one or both of which were present in 58% of European families (52/89) and 15% of non-European families (3/20). Login to comment 99 ABCB11 p.Glu297Gly E297G was detected in 34 European families (41 alleles) and on one allele in both an African-American and a South Asian family. Login to comment 100 ABCB11 p.Asp482Gly D482G occurred in 20 European families (25 alleles) and on one allele in a Central Asian/Arab family. Login to comment 112 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly In 23 families homozygosity was associated with known consanguinity, while in 9 families, 2 copies of either E297G or D482G were found. Login to comment 113 ABCB11 p.Asp482Gly ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly ABCB11 p.Glu297Gly To assess effects of specific ABCB11 genotypes on expression of immunohistochemically detectable BSEP protein, families were grouped according to whether they carried 2 likely protein-truncating mutations, at least one missense mutation (E297G or D482G excluded), at least one copy of E297G, at least one copy of D482G, or only one identified mutation (Supplementary Tables 1A-E). Login to comment 116 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly Variability in BSEP expression was greatest when either of the 2 common European mutations, E297G or D482G, was present on one or both alleles (Supplementary Tables 1C-E). Login to comment 117 ABCB11 p.Glu297Gly Twenty-nine patients with at least one copy of E297G were immunostained; BSEP staining was not detected in 16 (55%), was deficient in 12 (41%), and was normal in 1. Login to comment 118 ABCB11 p.Asp482Gly For 14 patients with at least one copy of D482G, BSEP staining was not detected in 8 (57%), was abnormal in 3 (21%), and was normal in 3 (21%). Login to comment 142 ABCB11 p.Glu297Gly The exception was E297G, present on a single allele in 1 of 200 European white control chromosomes (http://pharmacogenetics.ucsf.edu),39 in keeping with the high frequency of this allele among European BSEP-deficient patients. Login to comment 150 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly ABCB11 p.Arg1153Cys ABCB11 p.Gly982Arg ABCB11 p.Arg1231Gln ABCB11 p.Ile541Leu ABCB11 p.Arg1231Trp ABCB11 p.Ala570Thr ABCB11 p.Arg487Pro ABCB11 p.Asn490Asp ABCB11 p.Val481Glu ABCB11 p.Gly562Asp ABCB11 p.Arg517His ABCB11 p.Thr463Ile ABCB11 p.Arg470Gln ABCB11 p.Gly410Asp ABCB11 p.Ala390Pro ABCB11 p.Asn515Thr ABCB11 p.Gln466Lys ABCB11 p.Phe548Tyr ABCB11 p.Ile512Thr ABCB11 p.Gly327Glu ABCB11 p.Thr242Ile ABCB11 p.Leu50Ser ABCB11 p.Arg313Ser ABCB11 p.Arg1128Cys ABCB11 p.Thr1210Pro ABCB11 p.Leu1242Ile ABCB11 p.Ser1154Pro ABCB11 p.Arg1153His ABCB11 p.Ala1110Glu ABCB11 p.Arg948Cys ABCB11 p.Asn979Asp ABCB11 p.Arg832Cys ABCB11 p.Leu413Trp ABCB11 p.Ile541Thr ABCB11 p.Gly766Arg ABCB11 p.Tyr157Cys ABCB11 p.Gly758Arg ABCB11 p.Thr1029Lys ABCB11 p.Tyr472Cys ABCB11 p.Gly1298Arg 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. Login to comment 156 ABCB11 p.Glu297Gly The intracellular loops contained 6 changes (13%), of which 3, including E297G, occurred in intracellu- Table 3. Login to comment 162 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly In 5 cases, the single mutations were splice-site changes or E297G/D482G. Login to comment 163 ABCB11 p.Asn490Asp ABCB11 p.Gln466Lys In only 2 families were novel missense mutations identified (Q466K, N490D). Login to comment 165 ABCB11 p.Gln466Lys Q466K was associated with abnormal BSEP staining (detrimental). Login to comment 166 ABCB11 p.Asn490Asp N490D was associated with normal staining; however, this mutation lies within NBF1, a region in which disease-associated mutations coexisted with retained BSEP staining (see following text). Login to comment 184 ABCB11 p.Tyr472* (C) Absent BSEP staining in patient 4, homozygote for ABCB11 mutation yielding Y472X. Login to comment 189 ABCB11 p.Arg832Cys (E) BSEP staining in patient 29, homozygote for ABCB11 mutation yielding R832C. Login to comment 194 ABCB11 p.Leu50Ser ABCB11 p.Ala1110Glu (G) BSEP staining in patient 47b, compound heterozygote for ABCB11 mutations yielding L50S and A1110E. Login to comment 207 ABCB11 p.Arg1153Cys ABCB11 p.Gly982Arg ABCB11 p.Arg575* ABCB11 p.Arg470Gln ABCB11 p.Arg1153His ABCB11 p.Ala1110Glu ABCB11 p.Arg948Cys ABCB11 p.Arg832Cys ABCB11 p.Arg520* ABCB11 p.Glu1302* Ten mutations occurred in multiple families: R470Q, R832C,33 R948C, A1110E, and R1231Q53 have now been reported in 2 families; R1090X2 in 3 families; G982R,1,2 R1153C,1,47 and R1153H in 4 families; and R575X in 6 families.1,2,32,45 Six common missense and nonsense changes occurred at non-CpG sites: R520X and A588V33 in 2 European families and E1302X and I541L33,54 in 3 European families each. Login to comment 208 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly By far most common, however, were E297G and D482G, at least one of which was present in 58% (52/89) of European and in 15% (3/20) of non-European families. Login to comment 209 ABCB11 p.Glu297Gly The population distribution of E297G, most frequent along the North European seaboard, suggests an origin in Northern Europe and spread southward through Central and Eastern Europe. Login to comment 211 ABCB11 p.Asp482Gly In contrast, D482G likely originated in Central or Eastern Europe, with cases identified in Polish, Austrian, Slovak, Czech, Hungarian, and Russian families. Login to comment 219 ABCB11 p.Tyr472* ABCB11 p.Ile541Thr ABCB11 p.Tyr472Cys Mutation clusters include Y472C, Y472X,28 and I541L33,54/I541T. Login to comment 220 ABCB11 p.Arg303Lys Four different changes occurred at, or adjacent to, the 5= splice site of intron 9: R303K, c.908af9;1delG,1,33 c.908af9;1Gb0e;T,28 and c.908af9;1Gb0e;A. Login to comment 222 ABCB11 p.Glu297Gly ABCB11 p.Ala570Thr BSEP deficiency represents a phenotypic continuum between progressive early-onset1 disease and remitting, and late-onset, phenotypes.3-7 Eleven different mutations have been reported in BSEP deficiency disease clinically assessed as intermediate6 or mild in severity.4,5,7 Three of these, E297G, A570T, and c.2178af9;1Gb0e;A, have also been found in progressive familial intrahepatic cholestasis. Login to comment 225 ABCB11 p.Glu297Gly That homozygosity for E297G is seen in discrepant phenotypes strongly indicates that environment and genetic background also play roles. Login to comment 231 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly Residual staining was most striking in patients with E297G or D482G, with some seen in 45% of patients (19/42) carrying at least one of these alleles. Login to comment 233 ABCB11 p.Ile541Leu ABCB11 p.Asn490Asp ABCB11 p.Gly562Asp ABCB11 p.Arg517His ABCB11 p.Asn515Thr ABCB11 p.Gln466Lys ABCB11 p.Phe548Tyr ABCB11 p.Leu50Ser ABCB11 p.Ala1110Glu ABCB11 p.Arg832Cys Abnormal BSEP staining was seen with L50S, Q466K, N515T, R517H, I541L, and F548Y and normal with N490D, G562D, R832C, and A1110E. Login to comment 234 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly Because most of these were found in combination with E297G or D482G, their individual effects could not be assessed. Login to comment