Primary bile acid malabsorption is associated with congenital diarrhea, steatorrhea, and a block in the intestinal return of bile acids in the enterohepatic circulation. Mutations in the ileal apical sodium‐dependent bile acid transporter (ASBT; SLC10A2) can cause primary bile acid malabsorption but do not appear to account for most familial cases. Another major transporter involved in the intestinal reclamation of bile acids is the heteromeric organic solute transporter alpha‐beta (OSTα‐OSTβ; SLC51A‐SLC51B), which exports bile acid across the basolateral membrane. Here we report the first patients with OSTβ deficiency, clinically characterized by chronic diarrhea, severe fat soluble vitamin deficiency, and features of cholestatic liver disease including elevated serum gamma‐glutamyltransferase activity. Whole exome sequencing revealed a homozygous single nucleotide deletion in codon 27 of SLC51B, resulting in a frameshift and premature termination at codon 50. Functional studies in transfected cells showed that the SLC51B mutation resulted in markedly reduced taurocholic acid uptake activity and reduced expression of the OSTα partner protein. Conclusion: The findings identify OSTβ deficiency as a cause of congenital chronic diarrhea with features of cholestatic liver disease. These studies underscore OSTα‐OSTβ's key role in the enterohepatic circulation of bile acids in humans. (Hepatology 2017).

中文翻译：

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先天性腹泻两兄弟的有机溶质转运蛋白-β (SLC51B) 缺乏症及胆汁淤积的特点


原发性胆汁酸吸收不良与先天性腹泻、脂肪泻和肠肝循环中胆汁酸回流受阻有关。回肠顶端钠依赖性胆汁酸转运蛋白（ASBT；SLC10A2）的突变可导致原发性胆汁酸吸收不良，但似乎不能解释大多数家族性病例。参与胆汁酸肠道回收的另一个主要转运蛋白是异聚有机溶质转运蛋白 α-β（OSTα-OSTβ；SLC51A-SLC51B），它跨基底外侧膜输出胆汁酸。在此，我们报告了第一例 OSTβ 缺乏症患者，其临床特征为慢性腹泻、严重脂溶性维生素缺乏以及胆汁淤积性肝病的特征，包括血清 γ-谷氨酰转移酶活性升高。全外显子组测序揭示了 SLC51B 密码子 27 中的纯合单核苷酸缺失，导致密码子 50 处发生移码和提前终止。转染细胞的功能研究表明，SLC51B 突变导致牛磺胆酸摄取活性显着降低，并减少 OSTα 的表达伴侣蛋白。结论：研究结果确定 OSTβ 缺乏是导致以胆汁淤积性肝病为特征的先天性慢性腹泻的原因。这些研究强调了 OSTα-OSTβ 在人类胆汁酸肠肝循环中的关键作用。 （肝病学 2017）。