Carlton Victoria E H, Harris Baruch Z, Puffenberger Erik G, Batta A K, Knisely A S, Robinson Donna L, Strauss Kevin A, Shneider Benjamin L, Lim Wendell A, Salen Gerald, Morton D Holmes, Bull Laura N
Liver Center Laboratory and Department of Medicine, San Francisco General Hospital, University of California San Francisco, California 94110, USA.
Nat Genet. 2003 May;34(1):91-6. doi: 10.1038/ng1147.
Familial hypercholanemia (FHC) is characterized by elevated serum bile acid concentrations, itching, and fat malabsorption. We show here that FHC in Amish individuals is associated with mutations in tight junction protein 2 (encoded by TJP2, also known as ZO-2) and bile acid Coenzyme A: amino acid N-acyltransferase (encoded by BAAT). The mutation of TJP2, which occurs in the first PDZ domain, reduces domain stability and ligand binding in vitro. We noted a morphological change in hepatic tight junctions. The mutation of BAAT, a bile acid-conjugating enzyme, abrogates enzyme activity; serum of individuals homozygous with respect to this mutation contains only unconjugated bile acids. Mutations in both TJP2 and BAAT may disrupt bile acid transport and circulation. Inheritance seems to be oligogenic, with genotype at BAAT modifying penetrance in individuals homozygous with respect to the mutation in TJP2.
家族性高胆汁酸血症（FHC）的特征是血清胆汁酸浓度升高、瘙痒和脂肪吸收不良。我们在此表明，阿米什人群中的FHC与紧密连接蛋白2（由TJP2编码，也称为ZO-2）和胆汁酸辅酶A：氨基酸N-酰基转移酶（由BAAT编码）的突变有关。TJP2的突变发生在第一个PDZ结构域，在体外降低了结构域稳定性和配体结合能力。我们注意到肝脏紧密连接出现形态学变化。BAAT作为一种胆汁酸结合酶，其突变会消除酶活性；该突变纯合个体的血清中仅含有未结合的胆汁酸。TJP2和BAAT的突变都可能破坏胆汁酸的转运和循环。遗传方式似乎是寡基因的，BAAT的基因型会改变TJP2突变纯合个体的外显率。
