Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT
Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT
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DOI：
10.1038/ng1147
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发表时间：
2003-05-01
期刊：
影响因子：
30.8
通讯作者：
Bull, LN
中科院分区：
文献类型：
--
作者：
Carlton, VEH;Harris, BZ;Bull, LN
家族性高胆血症（FHC）的特征是血清胆汁酸浓度升高、瘙痒和脂肪吸收不良（1，2）。我们在这里表明，在阿米什人FHC与紧密连接蛋白2（由TJP 2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。发生在第一个PDZ结构域中的TJP 2突变降低了体外结构域稳定性和配体结合。我们注意到肝脏紧密连接的形态学变化。BAAT是一种胆汁酸结合酶（3），其突变可使酶活性丧失;该突变纯合子个体的血清中仅含有未结合的胆汁酸。TJP 2和BAAT的突变可能会破坏胆汁酸的转运和循环。遗传似乎是寡基因的，在BAAT基因型修饰的个体中，TJP 2突变是纯合的。
Familial hypercholanemia (FHC) is characterized by elevated serum bile acid concentrations, itching, and fat malabsorption(1,2). 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(3), 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.