ABCMdb

PMID: 22609309

Gonzales E, Grosse B, Cassio D, Davit-Spraul A, Fabre M, Jacquemin E
Successful mutation-specific chaperone therapy with 4-phenylbutyrate in a child with progressive familial intrahepatic cholestasis type 2.
J Hepatol. 2012 Sep;57(3):695-8. doi: 10.1016/j.jhep.2012.04.017. Epub 2012 May 16., [PubMed]

Sentences

No. Mutations Sentence Comment

3 ABCB11 p.Thr1210Pro After an in vitro study in a hepatocellular polarized line, we tested 4-PB treatment in a child with a homozygous p.T1210P BSEP mutation. Login to comment 4 ABCB11 p.Thr1210Pro Methods: Can 10 cells were transfected with plasmids encoding wild type Bsep (Bsepwt ) and mutated p.T1210P Bsep (BsepT1210P ), both tagged with GFP. Login to comment 10 ABCB11 p.Thr1210Pro Also, canalicular expression of p.T1210P BSEP mutant was partially corrected as was biliary bile acid excretion. Login to comment 24 ABCB11 p.Thr1210Pro Herein, we report on the first experience of 4-PB therapy in a patient with PFIC2 carrying a homozygous ABCB11 missense mutation (p.T1210P) leading to mistargeting and intracellular retention of the BSEP mutant. Login to comment 33 ABCB11 p.Thr1210Pro Furthermore, canalicular expression of p.T1210P BSEP mutant was partially corrected as was biliary bile acid excretion. Login to comment 37 ABCB11 p.Thr1210Pro The p.T1210P mutation was identified in both alleles of ABCB11 and BSEP liver immunostaining was negative. Login to comment 45 ABCB11 p.Thr1210Pro Patient`s mutation p.T1210P was introduced in a plasmid encoding a rat Bsep-green fluorescent protein (GFP) fusion protein [3], with the following primer forward 50 -GCTCCCA- GAGAAATATGAACCTAATGTTGGGATCCAGGGC-30 , using QuickChange Lightning Site-Directed Mutagenesis kit (Stratagene, USA) according to manufacturer`s instructions. Login to comment 93 ABCB11 p.Thr1210Pro Patient homozygous p.T1210P mutation of ABCB11 Before 4-PB Time of follow-up with 4-PB 1 month 3 months 8 months# 8 months + 1 week 12 months Itching (day-night) 8-10 5-7 1-3 6-10 5-7 1-3 Bile acids (N <10 &#b5;mol/L) 493 389 246 524 310 237 Total bilirubin (N <17 &#b5;mol/L) 200 69 14 49 19 11 ALT (N <35 IU/L) 125 55 51 66 27 19 PT (N >70%) 62 96 100 57 87 97 Factor V (N >80%) 68 78 83 87 100 83 Albumin (N >35 g/L) 30 36 41 39 n.a. 42 4-PB: mg/kg/d (total dose/day) none 200 (3 g) 267 (4 g) 134# (2 g)# 500 (8 g) 500 (8 g) PFIC2, progressive familial intrahepatic cholestasis type 2; ALT, alanine amino transferase; n.a., not available; PT, prothrombin time; 4-PB, 4-phenylbutyrate. Login to comment 109 ABCB11 p.Thr1210Pro Taken together, these results suggest that cholestasis and biliary bile acid secretion improvement observed in the patient likely relie on an effect of 4-PB on the mistrafficking of p.T1210P BSEP mutant, resulting in an increased cell-surface expression. Login to comment