Genetic association of the glycine cleavage system genes and myelomeningocele

Abstract

Background Neural tube defects (NTDs) are one of the most common congenital birth defects, with myelomeningocele (MM) being the most severe form compatible with life. Recent studies show a link between mitochondrial folate one carbon metabolism and NTDs via the glycine cleavage system (GCS). We hypothesize that single nucleotide polymorphisms (SNPs) and novel variants in the coding regions of the GCS genes increase the risk for MM. Methods DNA was obtained from 96 subjects with MM born before the United States mandated folic acid fortification of grains in 1998. Primers were designed for PCR amplification and sequencing of all exons in the AMT gene, one of four genes in the GCS, followed by identification of SNPs and novel variants. An additional 252 MM subjects underwent whole exome sequencing to examine all four GCS genes (aminomethyltransferase, glycine dehydrogenase, glycine cleavage system protein-H, and dihydrolipoamide dehydrogenase). Results We identified six novel, heterozygous variants in the AMT gene with three predicted to be deleterious to AMT function (p.Val7Leu, p.Pro251Arg, and p.Val380Met). Five extremely rare, known heterozygous variants were found in the AMT gene and one in the GLDC gene. No novel variants in the exons of the other two GCS genes (DLD and GCSH) were identified. Conclusions We identified novel and rare, known variants in two of the four GCS genes that may contribute to the development of MM. Consistent with previous findings, the current study provides additional support that genetic variations in GCS genes contribute to the risk of NTDs.

A targeted sequencing panel identifies rare damaging variants in multiple genes in the cranial neural tube defect, anencephaly

“…7 More recently, several candidate variants were identified in AMT and GLDC, 2 of the genes constituting the mitochondrial GCS. 10,32 In the present study, we identified a novel missense variant affecting the catalytic domain of the MTHFR gene. This patient additionally carried the c.677C>T variant, and a rare missense variant (c.2203G>T) in the GLDC gene.…”

“…30 GLDC encodes a component of the glycine cleavage system (GCS) in mitochondrial folate one-carbon metabolism, which has previously been implicated in both mouse and human NTDs. 10,11,31,32 Another individual with anencephaly (706F07) was heterozygous for a missense variant (c.200C>T; p.…”

Maternal nutrient intake and fetal gastroschisis: A case‐control study

“…Threonine is an essential amino acid that is used in the body for tissue protein synthesis, mucin production by the enterocytes of the intestine, and as a precursor for glycine (Shah, Northrup, Hixson, Morrison, & Au, ). Glycine was recently shown to be involved in the etiology of neural tube defects (Ouyang, Li, Liu, Chang, & Wu, ).…”

Approaches to studying the genomic architecture of complex birth defects

“…57,58 Furthermore, variants in AMT and GLDC that may contribute to human NTD risk have been identified in several studies. [56][57][58][59] After folates are transported to mitochondria, they are oxidized to formate by the actions of mitochondrial enzymes MTHFD2/2L…”