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

Abstract

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.

• Authors: Xi Liu, Yu Li, Menghan Wang, Xiaojun Wang, Limin Zhang, Tao Peng, Wenping Liang, Zhe Wang, Hong Lu
• Journal: Aging (Aging (Albany NY)) Vol. 13 Issue 1 Pg. 1176-1185 (12 03 2020) ISSN: 1945-4589 [Electronic] United States
• PMID: 33290257 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Muscle Relaxants, Central
• Vitamin B Complex
• 5,11-methenyltetrahydrohomofolate
• Folic Acid
• Methionine
• MTHFR protein, human
• Methylenetetrahydrofolate Reductase (NADPH2)
• Proteasome Endopeptidase Complex
• Baclofen
• Vitamin B 12

Topics

• Adolescent
• Alleles
• Ataxia (physiopathology)
• Baclofen (therapeutic use)
• Brain (diagnostic imaging)
• Cognitive Dysfunction (physiopathology)
• Female
• Folic Acid (analogs & derivatives, therapeutic use)
• Homocystinuria (diagnosis, drug therapy, genetics, physiopathology)
• Humans
• Magnetic Resonance Imaging
• Methionine (therapeutic use)
• Methylenetetrahydrofolate Reductase (NADPH2) (deficiency, genetics, metabolism)
• Muscle Hypertonia (drug therapy, physiopathology)
• Muscle Relaxants, Central (therapeutic use)
• Muscle Spasticity (diagnosis, drug therapy, genetics, physiopathology)
• Mutation, Missense
• Neural Conduction
• Polymorphism, Single Nucleotide
• Proteasome Endopeptidase Complex
• Proteolysis
• Psychotic Disorders (diagnosis, drug therapy, genetics, physiopathology)
• Reflex, Abnormal (physiology)
• Spine (diagnostic imaging)
• Vitamin B 12 (therapeutic use)
• Vitamin B Complex (therapeutic use)