Low Folate Concentration Impacts Mismatch Repair Deficiency in Neural Tube Defects

Abstract

Aim: To know the cause of sequence variants in neural tube defect (NTD). Materials & methods: We sequenced genes implicated in neural tube closure (NTC) in a Chinese cohort and elucidated the molecular mechanism-driving mutations. Results: In NTD cases, an increase in specific variants was identified, potentially deleterious rare variants harbored in H3K36me3 occupancy regions that recruits mismatch repair (MMR) machinery. Lower folate concentrations in local brain tissues were also observed. In neuroectoderm cells, folic acid insufficiency attenuated association of Msh6 to H3K36me3, and reduced bindings to NTC genes. Rare variants in human NTDs were featured by MMR deficiency and more severe microsatellite instability. Conclusion: Our work suggests a mechanistic link between folate insufficiency and MMR deficiency that correlates with an increase of rare variants in NTC genes.

Keywords::

• DNA repair
• folate insufficiency
• H3K36me3
• histone modification
• mismatch repair deficiency
• Msh6
• neural tube closure
• neural tube defect
• rare variant
• sequencing

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.comhttp://doi/suppl/10.2217/epi-2019-0279

Financial & competing interests disclosure

The work was supported by Ministry of Science and Technology of the PR China, National ‘973’ project (2013CB945404); the National Natural Science Foundation of China (nos. 81471163; 81771584; 81430005; 81701441), CAMS Initiative for Innovative Medicine (2016-I2M-1-008); Beijing Special Commonweal Found for Municipal Medical Research Institute Reform and Development (Beijing Medical Research 2016-04), MOE Chang Jiang Scholars Program (No. J201416). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

The work was supported by Ministry of Science and Technology of the PR China, National ‘973’ project (2013CB945404); the National Natural Science Foundation of China (nos. 81471163; 81771584; 81430005; 81701441), CAMS Initiative for Innovative Medicine (2016-I2M-1-008); Beijing Special Commonweal Found for Municipal Medical Research Institute Reform and Development (Beijing Medical Research 2016-04), MOE Chang Jiang Scholars Program (No. J201416). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.