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Oncotarget. 2017 Jul 19;8(33):55216-55229. doi: 10.18632/oncotarget.19377. eCollection 2017 Aug 15.

A missense mutation in TCN2 is associated with decreased risk for congenital heart defects and may increase cellular uptake of vitamin B12 via Megalin.

Author information

Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development, Fudan University, Shanghai 200011, China.
Institute of Genetics, School of Basic Medical Sciences, Lanzhou University, Lanzhou City 730000, China.
Key Laboratory of Reproduction Regulation of NPFPC, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai 200032, China.
Department of Pediatrics, University of Texas at Austin Dell Medical School, Austin, TX 78701, USA.
Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Jiangwan Campus, Shanghai 200438, China.
Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan 250022, China.
Children's Hospital Fudan University, Shanghai 201102, China.
Contributed equally


Deregulation of folate and vitamin B12 (VB12) metabolism contributes to the risk of congenital heart defects (CHDs). Transcobalamin (TCN2) is essential for transporting VB12 from blood to cells as TCN2-bound VB12 (holo-TC) is the only form for somatic cellular uptake. In this study, we performed an association study between common polymorphisms in 46 one carbon metabolism genes and CHD in 412 CHDs and 213 controls. Only two significant association signals in coding regions were identified: FTCD c.1470C>T & TCN2 c.230A>T. The only missense mutation, TCN2 c.230A>T, was further validated in 412 CHDs and 1177 controls. TCN2 c.230T is significantly associated with reduced CHD risk in North Chinese (odds ratio = 0.67, P = 4.62e-05), compared with the 230A allele. Interestingly, the mean level of plasma holo-TC in women with the TA genotype was 1.77-fold higher than that in women with the AA genotype. Further analysis suggested that c.230A>T enhanced the cellular uptake of holo-TC via the LRP2 receptor. Our results determined that a functional polymorphism in TCN2 contributes to the prevalence of CHDs. TCN2 c.230A>T is significantly associated with a reduced CHD risk, likely due to TCN2 c.230T improving the interaction between holo-TC and its LRP2 receptor.


LRP2; TCN2; congenital heart defects; holo-TC; vitamin B12

Conflict of interest statement

CONFLICTS OF INTEREST The authors declared no conflicts of interest.

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