Congenital Heart Disease and Genetic Changes in Folate/Methionine Cycles

Abstract

Congenital heart disease is one of the most common congenital malformations and thus represents a considerable public health burden. Hence, the identification of individuals and families with an increased genetic predisposition to congenital heart disease (CHD) and its possible prevention is important. Even though CHD is associated with the lack of folate during early pregnancy, the genetic background of folate and methionine metabolism perturbations and their influence on CHD risk is not clear. While some genes, such as those coding for cytosolic enzymes of folate/methionine cycles, have been extensively studied, genetic studies of folate transporters (de)glutamation enzymes and mitochondrial enzymes of the folate cycle are lacking. Among genes coding for cytoplasmic enzymes of the folate cycle, MTHFR, MTHFD1, MTR, and MTRR have the strongest association with CHD, while among genes for enzymes of the methionine cycle BHMT and BHMT2 are the most prominent. Among mitochondrial folate cycle enzymes, MTHFD2 plays the most important role in CHD formation, while FPGS was identified as important in the group of (de)glutamation enzymes. Among transporters, the strongest association with CHD was demonstrated for SLC19A1.

Keywords: congenital heart disease; folate; genetics; methionine; transporters.

Figure 1

The folate and methionine metabolism in cytoplasm and mitochondria. Influx transporters are shown in green, efflux transporters in dark green, enzymes involved in glutamation in orange, cytoplasmic enzymes of the folate cycle in red, enzymes of the methionine cycle in blue, and mitochondrial enzymes of the folate cycle in purple. ATP Binding Cassette Subfamily C Member 1 (ABCC1), ATP Binding Cassette Subfamily C Member 3 (ABCC3), ATP Binding Cassette Subfamily B Member 1 (ABCB1), solute carrier family 19 member 1 (SLC19A1), solute carrier family 46 member 1 (SLC46A1), folate receptor α (FOLR1), folate receptor β (FOLR2), folate receptor γ (FOLR3), γ-glutamyl hydrolase (GGH), folate hydrolase 1 (FOLH1), folylpolyglutamate synthase (FPGS), dihydrofolate reductase (DHFR), methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1 (MTHFD1), aldehyde dehydrogenase 1 family member L1 (ALDH1L1), serine hydroxymethyltransferase 1 (SHMT1), methenyltetrahydrofolate synthetase (MTHFS), formimidoyltransferase cyclodeaminase (FTCD), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), methylenetetrahydrofolate reductase (MTHFR), betaine-homocysteine S-methyltransferase (BHMT), betaine-homocysteine S-methyltransferase 2 (BHMT2), methionine adenosyltransferase 2A (MAT2A), glycine N-methyltransferase (GNMT), DNA methyltransferase 3 β (DNMT3B), adenosylhomocysteinase-like 1 (AHCYL1), cystathionine β-synthase (CBS), methylenetetrahydrofolate dehydrogenase 2, methenyltetrahydrofolate cyclohydrolase (MTHFD2), serine hydroxymethyltransferase 2 (SHMT2), methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L), aldehyde dehydrogenase 1 family member L2 (ALDH1L2), dihydrofolate (DHF), tetrahydrofolate (THF), S-adenosyl methionine (SAM), and S-adenosyl homocysteine (SAH), the dashed line represents the regeneration of MTR by MTRR.