关键词： MTHFR deficiency molecular mechanisms pathogenic mutation proteasome degradation single nucleotide polymophorism

Mesh ： 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

来  源：   DOI：10.18632/aging.202256   PDF(Pubmed)

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.
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