Clinical and molecular characterization of four patients with NTCP deficiency from two unrelated families harboring the novel SLC10A1 variant c.595A>C (p.Ser199Arg)
Clinical and molecular characterization of four patients with NTCP deficiency from two unrelated families harboring the novel SLC10A1 variant c.595A>C (p.Ser199Arg)
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DOI：
10.3892/mmr.2019.10763
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发表时间：
2019-12-01
影响因子：
3.4
通讯作者：
Song, Yuan-Zong
中科院分区：
文献类型：
--
作者：
Li, Hua;Deng, Mei;Song, Yuan-Zong
牛磺胆酸钠共转运多肽（NTCP）是由溶质载体家族10成员1（SLC 10A 1）编码的载体蛋白，在肝细胞的基底外侧膜中表达，其负责将胆汁酸从血浆摄取到肝细胞中。2015年描述了第一例NTCP缺乏症患者。文献中报告了有限数量的此类患者，其基因型和表型特征需要进一步研究。本研究调查了来自两个无关家族的4例NTCP缺乏症患者。对患者进行SLC 10A 1基因分析，结果显示所有患者均为c.800C>T（p.Ser267Phe）和c.595A>C（p.Ser199Arg）SLC 10A 1变体的复合杂合子。据作者所知，后一种变体以前从未报道过。对50名健康个体的进一步分析没有发现携带者。c.595A>C（p.Ser199Arg）变异体与高胆固醇血症共分离，与同源肽相比，其氨基酸相对保守。此外，SWISS-MODEL预测表明，突变影响了NTCP分子的构象。4例患者表现出不同程度的高胆血症，同时观察到2例儿童患者的血浆总胆汁酸（TBA）水平呈下降趋势，1例成人患者的TBA水平偶尔正常。结果表明NTCP缺乏症为常染色体隐性遗传，支持NTCP在从血浆中摄取胆汁酸中的主要作用，并表明肝脏摄取胆汁酸可能通过NTCP摄取以外的方式发生。此外，新的错义突变c.595A>C（p.Ser199Arg）丰富了SLC 10A 1的突变谱，有望成为NTCP缺陷症分子诊断和遗传咨询的新的遗传标记。
Sodium taurocholate cotransporting polypeptide (NTCP), a carrier protein encoded by solute carrier family 10 member 1 (SLC10A1), is expressed in the basolateral membrane of hepatocytes, where it is responsible for the uptake of bile acids from plasma into hepatocytes. The first patient with NTCP deficiency was described in 2015. A limited number of such patients have been reported in the literature and their genotypic and phenotypic features require further investigation. The current study investigated 4 patients with NTCP deficiency from two unrelated families. The patients were subjected to SLC10A1 genetic analysis and it was revealed that all patients were compound heterozygous for the c.800C>T (p.Ser267Phe) and c.595A>C (p.Ser199Arg) SLC10A1 variants. To the best of the authors' knowledge, the latter variant had not been previously reported. Further analysis in 50 healthy individuals did not identify carriers. The c.595A>C (p.Ser199Arg) variant exhibited co-segregation with hypercholanemia and exhibited a relatively conserved amino acid when compared with homologous peptides. Moreover, SWISS-MODEL prediction revealed that the mutation affected the conformation of the NTCP molecule. The 4 patients demonstrated varying degrees of hypercholanemia while a downward trend in the plasma levels of total bile acids (TBA) in 2 pediatric patients and occasionally normal TBA level in an adult case were observed. The results indicated an autosomal recessive trait for NTCP deficiency, supported the primary role of NTCP in the uptake of bile acids from plasma and suggested that hepatic uptake of bile acids may occur by means other than NTCP uptake. Moreover, the novel missense variant c.595A>C(p.Ser199Arg) enriched the SLC10A1 mutation spectrum and may serve as a new genetic marker for the molecular diagnosis and genetic counseling of NTCP deficiency.