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Sci Rep. 2017 Aug 23;7(1):9214. doi: 10.1038/s41598-017-07012-2.

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

Liu R1, Chen C2,3, Xia X4, Liao Q5, Wang Q6, Newcombe PJ7, Xu S8, Chen M6, Ding Y9, Li X10, Liao Z11, Li F12, Du M13, Huang H14, Dong R15, Deng W16, Wang Y17, Zeng B18, Pan Q19, Jiang D20, Zeng H20, Sham P21,22,23,24, Cao Y25, Maxwell PH26, Gao ZL27,28, Peng L29,30, Wang Y31,32,33.

Author information

1
Fifth Affiliated Hospital, Sun Yat-sen University-BGI Laboratory, Department of Experimental Medicine, The Fifth Affiliated Hospital,Sun Yat-sen University, Zhuhai, China.
2
Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
3
Guangdong Key Laboratory of Liver Diseases, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
4
Methodist Hospital Research Institute, Weill Cornell School of Medicine, Houston, TX, 77030, USA.
5
BGI Genomics, BGI-Shenzhen, Shenzhen, 518083, China.
6
Center for Reproductive Medicine, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
7
MRC Biostatistics Unit, Cambridge, United Kingdom.
8
Chinese Academy of Sciences Key Laboratory of Computational Biology, Max Planck Independent Research Group on Population Genomics, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute for Biological Sciences, CAS, Shanghai, China.
9
Department of Orthopaedic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
10
Department of Endocrinology, Fudan Institute of Metabolic Disease, Zhongshan Hospital, Fudan University, Shanghai, China.
11
Department of Endocrinology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
12
Department of Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China.
13
Department of Pediatrics, First Af f iliated Hospital, Sun Yat-sen University, Guangzhou, China.
14
Department of Dermatology and Venereology, Third Af f iliated Hospital, Sun Yat-sen University, Guangzhou, China.
15
Department of Cardiology, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
16
Department of Dermatology, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou, China.
17
Center for Fetal Medicine, Department of Obstetrics and Gynecology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
18
Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China.
19
Center for Prenatal Diagnosis, Sixth Affiliated Hospital, Guangzhou Medical University, Qingyuan, China.
20
Department of Medical Genetics, Center for Genome Research, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
21
Centre for Genomic Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
22
Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong.
23
State Key Laboratory for Cognitive and Brain Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
24
Centre for Reproduction, Development and Growth, The University of Hong Kong, Pokfulam, Hong Kong.
25
Department of Pharmacology, Xinhua College, Sun Yat-sen University, Guangzhou, China.
26
School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom.
27
Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. zhilianggao@21cn.com.
28
Guangdong Key Laboratory of Liver Diseases, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. zhilianggao@21cn.com.
29
Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. pzp33@hotmail.com.
30
Guangdong Key Laboratory of Liver Diseases, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. pzp33@hotmail.com.
31
Fifth Affiliated Hospital, Sun Yat-sen University-BGI Laboratory, Department of Experimental Medicine, The Fifth Affiliated Hospital,Sun Yat-sen University, Zhuhai, China. ywzhong@hotmail.com.
32
Department of Medical Genetics, Center for Genome Research, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. ywzhong@hotmail.com.
33
Department of Pharmacology, Xinhua College, Sun Yat-sen University, Guangzhou, China. ywzhong@hotmail.com.

Abstract

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.

PMID:
28835676
PMCID:
PMC5569087
DOI:
10.1038/s41598-017-07012-2
[Indexed for MEDLINE]
Free PMC Article

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