Research Paper Volume 13, Issue 1 pp 1176—1185

The 1316T>C missenses mutation in MTHFR contributes to MTHFR deficiency by targeting MTHFR to proteasome degradation

Xi Liu1, *, , Yu Li2,3, *, , Menghan Wang1, *, , Xiaojun Wang1, , Limin Zhang1, , Tao Peng1, , Wenping Liang2,3, , Zhe Wang2,3, , Hong Lu1, ,

  • 1 Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
  • 2 The National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
  • 3 Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100053, China
* Equal contribution

Received: May 23, 2020       Accepted: October 27, 2020       Published: December 3, 2020
How to Cite

Copyright: © 2020 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare hereditary disease characterized by defects in folate and homocysteine metabolism. Individuals with inherited MTHFR gene mutations have a higher tendency to develop neurodegeneration disease as Alzheimer’ disease and atherosclerosis. MTHFR is a rate-limiting enzyme catalyzing folate production, various SNPs/mutations in the MTHFR gene have been correlated to MTHFR deficiency. However, the molecular mechanisms underpinning the pathogenic effects of these SNPs/mutations have not been clearly understood. In the present study, we reported a severe MTHFR deficiency patient with late-onset motor dysfunction and sequenced MTHFR gene exons of the family. The patient carries an MD-associating SNP (rs748289202) in one MTHFR allele and the rs545086633 SNP with unknown disease relevance in the other. The rs545086633 SNP (p.Leu439Pro) results in an L439P substitution in MTHFR protein, and drastically decreases mutant protein expression by promoting proteasomal degradation. L439 in MTHFR is highly conserved in vertebrates. Our study demonstrated that p.Leu439Pro in MTHFR is the first mutation causing significant intracellular defects of MTHFR, and rs545086633 should be examined for the in-depth diagnosis and treatment of MD.


CMV: cytomegalovirus; FAD: Flavin Adenine Dinucleotide; MD: reductase deficiency; MTHFR: 5,10-methylenetetrahydrofolate; MMSE: Mini-Mental State Examination; MoCA: Montreal cognitive assessment; MTHFR: 5,10-methylenetetrahydrofolate reductase; SNP: single nucleotide polymorphism; THF: tetrahydrofolate; NADPH: nicotinamide adenine dinucleotide phosphate.