In the present study, a multi-institutional research team has developed a novel folic acid-resistant neural tube defect mouse model of the human condition by silencing the Slc25a32 gene, and, in most of the mutant mice, neural tube defects can be prevented by formate supplementation
Maternal folic acid supplementation has reduced the prevalence of neural tube defects, one of the most common structural malformations in people, by up to 80%.
In this study, a multi-institutional research team has developed a novel folic acid-resistant neural tube defect mouse model of the human condition by silencing the Slc25a32 gene, and, in most of the mutant mice, neural tube defects can be prevented by formate supplementation.
A parallel genetic study of individuals with neural tube defects found a patient carrying a non-functional mutation of the SLC25A32 gene. Together, these findings support the search for supplements that might prevent folic acid-resistant human neural tube defects in the future.
The success obtained with folic acid supplementation suggested that there might be other nutrients that could prevent neural tube defect cases that do not respond to folic acid. To find these nutrients, Finnell and his colleagues studied the metabolic pathway involving folic acid.
"Lacking enough folic acid inhibits DNA synthesis and cell proliferation and can have serious consequences, especially in the growing embryo which is engaged in active cell proliferation to develop a complete baby," Finnell said. "Folic acid deficiency in the embryo, together with genetic and environmental factors, can result in failed closure of the neural tube and lead to defects."
As the researchers studied the metabolic pathway involving folic acid, called one carbon metabolism, they focused on formate, a compound derived from folic acid in a cellular organelle called the mitochondria that also contributes to DNA synthesis.
"In our study, we asked whether disrupting formate synthesis by silencing the Slc25a32 gene that transports the precursors of formate into the mitochondria would also result in neural tube defects in mice," said first author Dr. Yunping Lei.
"When we genetically engineered mice to lack the formate transport protein produced by the Slc25a32 gene, all of the mutant mice had neural tube defects. When we provided pregnant mice with extra formate, we were able to prevent neural tube defects in 78% of the offspring carrying a defective Slc25a32 gene," he added.
To determine whether the findings in mice could be connected to human neural tube defects, the researchers conducted genomic studies in a cohort of patients with this condition and found one individual carrying a non-functional variant of the SLC25A32 gene.
"My lab is all about preventing preventable birth defects," Finnell said. "Even though we do fortify foods with folic acid, there are still babies born with neural tube defects. Folic acid has been a major public health advance, but the problem has not disappeared. We cannot lose sight of the fact that babies can still be born with neural tube defects even when the mothers take folic acid supplements."