ABCMdb

PMID: 20232290

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., [PubMed]

Sentences

No. Mutations Sentence Comment

74 ABCB11 p.Val444Ala ABCB11 p.Val444Ala ABCB11 p.Met677Val The 24 remaining mutations were single missense substitutions. In addition to the 41 disease-causing mutations, we found three other variants (p.V444A, p.G319G, p.M677V) considered SNPs.7,27 The p.V444A mutation was present on 44% of PFIC alleles Table 1. Login to comment 79 ABCB11 p.Val444Ala †Patient harboring the heterozygous ABCB11 mutation p.V444A. Login to comment 80 ABCB11 p.Val444Ala †Patient harboring the heterozygous ABCB11 mutation p.V444A. Login to comment 89 ABCB11 p.Arg698His ABCB11 p.Arg698His The p.R698H mutation previously reported as a possible rare SNP was identified in three children.11,12 However, BSEP canalicular staining was negative or focal negative in these three patients, and biliary BA concentration was low in one of them; two were heterozygous for p.R698H and one was heterozygous compound. Login to comment 90 ABCB11 p.Arg698His ABCB11 p.Arg698His The p.R698H mutation previously reported as a possible rare SNP was identified in three children.11,12 However, BSEP canalicular staining was negative or focal negative in these three patients, and biliary BA concentration was low in one of them; two were heterozygous for p.R698H and one was heterozygous compound. Login to comment 93 ABCB11 p.Arg1090* ABCB11 p.Arg1090* ABCB11 p.Tyr354* ABCB11 p.Tyr354* ABCB11 p.Tyr354* ABCB11 p.Tyr354* ABCB11 p.Tyr354* ABCB11 p.Tyr354* ABCB11 Mutations in PFIC2 Patients Family Mutation Allele 1 Mutation Allele 2 Biliary BA (N > 10 mmol/L) BSEP Liver Immunohistochemistry PFIC2 no. 1 p.R1090X p.R1090X 0.02 BSEP À PFIC2 no. 2 p.Y354X p.Y354X 0.02 BSEP À PFIC2 no. 3 p.Y354X p.Y354X 0.19 BSEP À PFIC2 no. 4 p.Y354X p.Y354X na na PFIC2 no. Login to comment 94 ABCB11 p.Gly982Arg ABCB11 p.Arg1090* ABCB11 p.Arg1090* ABCB11 p.Tyr354* ABCB11 p.Tyr354* ABCB11 p.Tyr354* ABCB11 p.Tyr354* ABCB11 p.Tyr354* ABCB11 p.Tyr354* ABCB11 p.Tyr354* ABCB11 Mutations in PFIC2 Patients Family Mutation Allele 1 Mutation Allele 2 Biliary BA (N > 10 mmol/L) BSEP Liver Immunohistochemistry PFIC2 no. 1 p.R1090X p.R1090X 0.02 BSEP À PFIC2 no. 2 p.Y354X p.Y354X 0.02 BSEP À PFIC2 no. 3 p.Y354X p.Y354X 0.19 BSEP À PFIC2 no. 4 p.Y354X p.Y354X na na PFIC2 no. Login to comment 95 ABCB11 p.Gly982Arg ABCB11 p.Tyr354* 5a‡ p.Y354X p.G982R 0.10 BSEP À PFIC2 no. Login to comment 96 ABCB11 p.Gly982Arg ABCB11 p.Arg415* ABCB11 p.Arg415* ABCB11 p.Tyr354* 5b‡ p.Y354X p.G982R na na PFIC2 no. Login to comment 97 ABCB11 p.Glu297Gly ABCB11 p.Glu297Gly ABCB11 p.Gly238Val ABCB11 p.Gly238Val ABCB11 p.Arg1128Cys ABCB11 p.Arg1128Cys ABCB11 p.Arg415* ABCB11 p.Arg415* ABCB11 p.Ser226Leu ABCB11 p.Ser226Leu 6† p.R415X p.R415X na na PFIC2 no. Login to comment 98 ABCB11 p.Gly238Val ABCB11 p.Gly238Val ABCB11 p.Arg1128Cys ABCB11 p.Arg1128Cys ABCB11 p.Arg1128Cys ABCB11 p.Arg1128Cys ABCB11 p.Ser226Leu ABCB11 p.Ser226Leu 7 20; p.S226L p.S226L na na PFIC2 no. 8 p.G238V p.G238V 0.06 BSEP À PFIC2 no. Login to comment 99 ABCB11 p.Glu297Gly ABCB11 p.Glu297Gly ABCB11 p.Arg1128Cys ABCB11 p.Arg1128Cys ABCB11 p.Thr1210Pro ABCB11 p.Thr1210Pro 9† p.E297G p.E297G 0.80 BSEP À PFIC2 no. 10a p.R1128C p.R1128C 0.10 BSEP À PFIC2 no. Login to comment 100 ABCB11 p.Arg1128Cys ABCB11 p.Arg1128Cys ABCB11 p.Ile420Thr 10b p.R1128C p.R1128C 0.58 BSEP À PFIC2 no. Login to comment 101 ABCB11 p.Glu297Gly ABCB11 p.Glu297Gly ABCB11 p.Arg698His ABCB11 p.Arg1231Trp ABCB11 p.Arg1128Cys ABCB11 p.Arg1128Cys ABCB11 p.Ala167Thr ABCB11 p.Ile420Thr ABCB11 p.Met62Lys ABCB11 p.Ile528* ABCB11 p.Ile112Thr 11† p.R1128C p.R1128C na na PFIC2 no. Login to comment 102 ABCB11 p.Gly982Arg ABCB11 p.Thr1210Pro ABCB11 p.Thr1210Pro ABCB11 p.Asp549Val ABCB11 p.Ala257Gly ABCB11 p.Ile182Lys 12† p.T1210P p.T1210P 0.11 BSEP À PFIC2 no. 13 c.3213 15 G>A p.A1192EfsX50 na BSEP 0; PFIC2 no. Login to comment 103 ABCB11 p.Ile420Thr ABCB11 p.Met183Thr ABCB11 p.Gly455Glu 14a† p.I420T p.I1061VfsX34 0.02 na PFIC2 no. Login to comment 104 ABCB11 p.Glu297Gly ABCB11 p.Glu297Gly ABCB11 p.Arg1153Cys ABCB11 p.Gly982Arg ABCB11 p.Gly982Arg ABCB11 p.Arg698His ABCB11 p.Asn591Ser ABCB11 p.Arg1231Trp ABCB11 p.Ala167Thr ABCB11 p.Ile420Thr ABCB11 p.Met62Lys ABCB11 p.Ile528* ABCB11 p.Ile112Thr ABCB11 p.Trp114Arg 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. Login to comment 105 ABCB11 p.Gly982Arg ABCB11 p.Arg698His ABCB11 p.Asp549Val ABCB11 p.Ala257Gly ABCB11 p.Ile182Lys ABCB11 p.Arg470* ABCB11 p.Tyr1041* 20† p.A257G p.G982R na na PFIC2 no. 21* p.I182K c.3213 15 G>A na BSEP À PFIC2 no. 22 p.D549V c.76 13 G>T na na PFIC2 no. Login to comment 106 ABCB11 p.Arg698His ABCB11 p.Met183Thr ABCB11 p.Gly455Glu ABCB11 p.Arg387His 23†,§ p.M183T p.G455E na na PFIC2 no. Login to comment 107 ABCB11 p.Glu297Gly ABCB11 p.Arg1153Cys ABCB11 p.Gly982Arg ABCB11 p.Gly982Arg ABCB11 p.Asn591Ser ABCB11 p.Trp114Arg ABCB11 p.Ser699Pro 24† p.R1153C c.3213 14 A>G 0.13 BSEP À PFIC2 no. 25* p.G982R p.Q101DfsX8 0.10 BSEP À PFIC2 no. 26* p.N591S þ p.V597V nf 0.39 BSEP À PFIC2 no. 27* p.G982R p.R1001R na BSEP À PFIC2 no. 28 p.L232CfsX9 nf na BSEP À PFIC2 no. 29 p.W114R nf 0.50 BSEP À PFIC2 no. Login to comment 108 ABCB11 p.Arg698His ABCB11 p.Arg470* ABCB11 p.Tyr1041* ABCB11 p.Arg387His ABCB11 p.Gly1116Phe 30† p.Y1041X nf 0.22 BSEP À PFIC2 no. 31* p.R470X nf na na PFIC2 no. 32* p.R698H nf na BSEP 6 PFIC2 no. Login to comment 109 ABCB11 p.Val444Ala ABCB11 p.Arg698His ABCB11 p.Arg387His 33†,‡ p.R698H nf na BSEP 6 PFIC2 no. 34 p.M1V p.R387H na na PFIC2 no. Login to comment 110 ABCB11 p.Glu297Gly ABCB11 p.Val444Ala ABCB11 p.Ser699Pro 35† p.E297G p.S699P na na PFIC2 no. Login to comment 111 ABCB11 p.Met677Val ABCB11 p.Arg387His ABCB11 p.Gly1116Phe 36†,k p.G1116F p.R387H na na Novel mutations described in this study are shown in bold. Login to comment 112 ABCB11 p.Val444Ala *Patient harboring the heterozygous ABCB11 mutation p.V444A. Login to comment 113 ABCB11 p.Val444Ala †Patient harboring the homozygous ABCB11 mutation p.V444A. Login to comment 114 ABCB11 p.Met677Val ‡Patient harboring the heterozygous ABCB11 mutation p.M677V. Login to comment 213 ABCB11 p.Glu297Gly *Patient harboring heterozygous BSEP mutation p.E297G. Login to comment 214 ABCB11 p.Glu297Gly †Patient harboring homozygous BSEP mutation p.E297G. Login to comment 217 ABCB11 p.Glu297Gly *Patient harboring heterozygous BSEP mutation p.E297G. Login to comment 218 ABCB11 p.Glu297Gly †Patient harboring homozygous BSEP mutation p.E297G. Login to comment 220 ABCB11 p.Glu297Gly ABCB11 p.Glu297Gly The only PFIC2 child with a total success of BD harbored homozygous mutation p.E297G and two PFIC2 children with a partial failure of BD were heterozygous for p.E297G mutation. Login to comment 224 ABCB11 p.Glu297Gly ABCB11 p.Glu297Gly The only PFIC2 child with a total success of BD harbored homozygous mutation p.E297G and two PFIC2 children with a partial failure of BD were heterozygous for p.E297G mutation. Login to comment 239 ABCB11 p.Val444Ala Five of these patients also harbored the p.V444A variant, which may lower the BSEP expression level.11 Mutations located outside the sequenced regions, such as in regulatory domains, or microdeletions of one or more exons cannot be excluded.7 Such defects could explain the phenotype of the PFIC? Login to comment 243 ABCB11 p.Val444Ala Five of these patients also harbored the p.V444A variant, which may lower the BSEP expression level.11 Mutations located outside the sequenced regions, such as in regulatory domains, or microdeletions of one or more exons cannot be excluded.7 Such defects could explain the phenotype of the PFIC? Login to comment 257 ABCB11 p.Glu297Gly ABCB11 p.Glu297Gly This lower BD response rate than in other reports might be due to a more advanced stage of liver fibrosis before BD was performed, because an absence of cirrhosis was previously thought to be predictive of success, and/or to how BD success or failure was defined.14,22,28-30 For example, pruritus relief was considered a BD success in a recent series and likely equals BD partial failure in our series.30 ABCB11 genotype could also have a predictive value because the PFIC2 patient with BD success had a homozygous p.E297G mutation and two other PFIC2 patients with BD partial failure harbored on one allele the p.E297G mutation.31 This mutant is known to be associated with impaired membrane trafficking but to retain some transport activity when correctly targeted.32 The mechanism involved in the recovery of normal BA secretion after BD in patients harboring this mutant protein is unknown but could be related to canalicular targeting of the mutated BSEP. Login to comment 261 ABCB11 p.Glu297Gly ABCB11 p.Glu297Gly This lower BD response rate than in other reports might be due to a more advanced stage of liver fibrosis before BD was performed, because an absence of cirrhosis was previously thought to be predictive of success, and/or to how BD success or failure was defined.14,22,28-30 For example, pruritus relief was considered a BD success in a recent series and likely equals BD partial failure in our series.30 ABCB11 genotype could also have a predictive value because the PFIC2 patient with BD success had a homozygous p.E297G mutation and two other PFIC2 patients with BD partial failure harbored on one allele the p.E297G mutation.31 This mutant is known to be associated with impaired membrane trafficking but to retain some transport activity when correctly targeted.32 The mechanism involved in the recovery of normal BA secretion after BD in patients harboring this mutant protein is unknown but could be related to canalicular targeting of the mutated BSEP. 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