Primary bile acid malabsorption caused by mutations in the ileal sodium-dependent bile acid transporter gene (SLC10A2)
Primary bile acid malabsorption caused by mutations in the ileal sodium-dependent bile acid transporter gene (SLC10A2)
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DOI：
10.1172/jci119355
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发表时间：
1997-04-15
影响因子：
15.9
通讯作者：
Dawson, PA
中科院分区：
文献类型：
--
作者：
Oelkers, P;Kirby, LC;Dawson, PA
原发性胆汁酸吸收不良（PBAM）是一种与先天性腹泻、脂肪肝、胆汁酸肠肝循环中断和血浆胆固醇水平降低相关的特发性肠道疾病。本研究克隆了人回肠Na+/胆汁酸协同转运蛋白基因（SLC 10A 2），并采用单链构象多态性分析方法筛选PBAM相关突变。在一个先天性PBAM家系中发现了4个多态性位点，其中一个等位基因编码A171 S错义突变和外显子3的供体剪接位点突变，另一个等位基因编码保守氨基酸位置L243 P和T262 M的两个错义突变。和双突变（L243 P/T262 M）不影响转运蛋白的表达或转运至质膜;然而，牛磺胆酸盐和其他胆汁酸的转运被消除。相反，A171 S突变对牛磺胆酸盐摄取没有影响，在104名未受影响的对照受试者中未检测到功能障碍性突变，而A171 S存在于该人群的28%中。这些发现确立了SLC 10A 2突变可引起PBAM，并强调了回肠Na+/胆汁酸共转运蛋白在胆汁酸的肠回收中的作用。
Primary bile acid malabsorption (PBAM) is an idiopathic intestinal disorder associated with congenital diarrhea, steatorrhea, interruption of the enterohepatic circulation of bile acids, and reduced plasma cholesterol levels. The molecular basis of PBAM is unknown, and several conflicting mechanisms have been postulated, In this study, we cloned the human ileal Na+/bile acid cotransporter gene (SLC10A2) and employed single-stranded conformation polymorphism analysis to screen for PBAM-associated mutations. Four polymorphisms were identified and sequenced in a family with congenital PBAM, One allele encoded an A171S missense mutation and a mutated donor splice site for exon 3, The other allele encoded two missense mutations at conserved amino acid positions, L243P and T262M, In transfected COS cells, the L243P, T262M, and double mutant (L243P/T262M) did not affect transporter protein expression or trafficking to the plasma membrane; however, transport of taurocholate and other bile acids was abolished, In contrast, the A171S mutation had no effect on taurocholate uptake, The dysfunctional mutations were not detected in 104 unaffected control subjects, whereas the A171S was present in 28% of that population, These findings establish that SLC10A2 mutations can cause PBAM and underscore the ileal Na+/bile acid cotransporter's role in intestinal reclamation of bile acids.