课件：婴儿郁胆分子机制初探.ppt

FIC1 deficiency BRIC 基因定位18q21-22 Houwen RH, 1994, Nat Genet 8:380 PFIC (Byler disease)基因定位18q21-22 Carlton VE, 1995, 4:1049-1053 PFIC遗传异质性，PFIC1 ATP8B1基因，编码的产物FIC1 Bull LN, Nat Genet 1998, 18:219 FIC1 deficiency (续) Greenland familial cholestasis, Asp554Asn Klomp LW, Hepatology, 2000,32:1337 各地的散发性病例 无家族史、父母非近亲婚配 欧洲、日本、中国台湾 新认识 PFIC1和BRIC 1有同一基因引起 PFIC多见缺失、移位、无义突变 BRIC多见错义突变 PFIC1和BRIC 1可表现为一连续过程 共同的临床特征 Low GGT in cholestasis Low GGT expression Defect of bile salt exportation BSEP deficiency 1997年，低GGT PFIC的第二个基因（沙特）被定位于2q24，因此这种被命名为PFIC2 Strautnieks SS. Am J Hum Genet. 61,630. 1998年， BSEP基因突变引起PFIC 2 Strautnieks SS. Nat Genet. 20,233. 2004 年，BRIC 2由ABCB11突变 PFIC多见缺失、移位、无义突变, BRIC多见错义突变 van Mil SWC, Gastroenterology, 127,379. PFIC 2 见于欧洲、日本、 中国等世界各地 Case 2 GA, A167I Case 3 CAG TAGExon 18 C2230T Q702Stop Case 5 Intron 22 (+3) Exon 7 T A 562 GT G188W Case 5 Intron 22 (+3) 紧邻剪切位点(ACCT) T to A Hum AAGATTACCTG Mus AAGATTACCTG Dog AAGATTACCTG Cow TAGATTACCTG Case AAGATAACCTG Case 7 Intron 6 T+63T/G (167) Low GGT in cholestasis Defect of bile salt exportation Defect of bile salt synthesis Bile acid synthetic defect 16 enzymes catalyze 17 reactions in bile acid synthesis from cholesterol Russell DW. Annu Rev Biochem 2003,72,137 Defects in different enzymes associate with neonatal cholestasis Delta(4)-3-oxosteroid 5beta-reductase(AKR1D1) Gonzales E, J Hepatol 2004,40,716 Oxysterol 7?-hydroxylase (CRP7B1) Setchell KDR, J Clin Invest 1998,102,1690 Bile acid synthetic defect -PFIC 4 2000, HSD3B7, chromosome 16p12-p11.2 Encoding 3-beta-hydroxy-delta-5-C27 steroid oxidoreductase (C27-3-BETA-HSD) Participate in all pathways of bile acid synthesis (7-alpha-hydroxylated sterols) 2 bp deletion in a Saudi boy with neonatal PIC Schwarz M. J Clin Invest 2000,106,1175 2003, confirmed in a Chilean family, a French family, a British and a Canadian family Cheng JB. J Cli