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Methylenetetrahydrofolate reductase dimer configuration and chromosome 21 nondisjunction

OBJECTIVE: Evidence suggests that dimer configuration of methylenetetrahydrofolate reductase (MTHFR) enzyme might be destabilized by specific position of C677T and A1298C polymorphisms in monomers. It has been observed that these polymorphisms may lead to stable (CCAA, CCAC, CCCC) and unstable (TTAA, CTAA, CTAA) enzyme dimer configurations. Based on evidence that lower folate dietary intake and maternal MTHFR polymorphisms might be a risk factor for trisomy 21, and that different mechanisms leads to meiotic stage of nondisjunction (meiosis I/II - MI/MII) we hypothesized that the trisomy 21 risk could be different for the particular meiotic stage. Thus, we aim to assess the association of the MTHFR enzyme dimer configuration and folate dietary intake with the stage of meiotic nondisjunction in mothers of children with maternally derived trisomy 21. METHODS: The study included 119 mothers of children with maternally derived trisomy 21. Meiotic stages of nondisjunction were determined using short tandem repeat markers. PCR-RFLP analysis was performed to detect MTHFR C677T and A1298C polymorphisms. Characteristic dietary and lifestyles habits were analyzed by specially created questionnaire. RESULTS: MI nondisjunction was observed in 86% (102/119) and MII nondisjunction in 14% (17/119) of cases. No differences were found between these two groups according to the dietary and lifestyles habits. Mothers with MI nondisjunction were significantly younger compared to mothers with MII nondisjunction (P=0.021). Increased frequency of the unstable MTHFR enzyme configuration (P=0.007) was found in the group of mothers with MI nondisjunction compared to mothers with MII nondisjunction. CONCLUSION: Our results suggest that unstable MTHFR enzyme configuration might be associated with maternal MI nondisjunction of chromosome 21. Further analyses on larger sample are needed to provide an answer to this question.

chromosome nondisjunction, Down syndrome, folate, functional interference, MTHFR gene polymorphism

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