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Homozygous p.Ser267Phe in SLC10A1 is associated with a new type of hypercholanemia and implications for personalized medicine.

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Liu, Ruihong 
Chen, Chuming 
Xia, Xuefeng 
Liao, Qijun 
Wang, Qiong 


SLC10A1 codes for the sodium-taurocholate cotransporting polypeptide (NTCP), which is a hepatocellular transporter for bile acids (BAs) and the receptor for hepatitis B and D viruses. NTCP is also a target of multiple drugs. We aimed to evaluate the medical consequences of the loss of function mutation p.Ser267Phe in SLC10A1. We identified eight individuals with homozygous p.Ser267Phe mutation in SLC10A1 and followed up for 8-90 months. We compared their total serum BAs and 6 species of BAs with 170 wild-type and 107 heterozygous healthy individuals. We performed in-depth medical examinations and exome sequencing in the homozygous individuals. All homozygous individuals had persistent hypercholanemia (P = 5.8 × 10-29). Exome sequencing excluded the involvement of other BA metabolism-associated genes in the hypercholanemia. Although asymptomatic, all individuals had low vitamin D levels. Of six adults that were subjected to bone mineral density analysis, three presented with osteoporosis/osteopenia. Sex hormones and blood lipids were deviated in all subjects. Homozygosity of p.Ser267Phe in SLC10A1 is associated with asymptomatic hypercholanemia. Individuals with homozygous p.Ser267Phe in SLC10A1 are prone to vitamin D deficiency, deviated sex hormones and blood lipids. Surveillance of these parameters may also be needed in patients treated with drugs targeting NTCP.



Adolescent, Adult, Alleles, Amino Acid Substitution, Bile Acids and Salts, Bone Density, Child, Female, Follow-Up Studies, Homozygote, Humans, Hypercholesterolemia, Lipid Metabolism, Male, Middle Aged, Organic Anion Transporters, Sodium-Dependent, Precision Medicine, Symporters, Exome Sequencing, Young Adult

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Scientific Reports

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Nature Publishing Group
Wellcome Trust (096956/Z/11/Z)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0514-10122)
This project is supported by the National Natural Science Foundation of China (31471193, 81570539, 81370535, 91331204 and 31525014). S.X. acknowledges financial support from the Strategic Priority Research Program (XDB13040100) and Key Research Program of Frontier Sciences (QYZDJ-SSW-SYS009) of the Chinese Academy of Sciences (CAS).