Identification of a Mutation in the PFKP as a Causative Factor in Prenatal Glycolysis Defects and Embryonic Myocardial Hypoplasia

Congenital heart disease (CHD) is the most common birth defect worldwide, which lacks effective early preventive methods due to limited knowledge of the genetic defects involved in its development. Through genetic analysis of families with congenital heart disease (CHD), we identified a genetic correlation between the R755W variant of the platelet isoform of phosphofructokinase 1 (PFKP) and myocardial hypoplasia. Furthermore, PFKP ^R754W/R754W and PFKP knockout mice exhibited a myocardial hypoplasia phenotype during embryonic development. Mechanistic studies further revealed that PFKP deficiency reduces embryonic cardiac glycolysis, leading to decreased cardiomyocyte proliferation due to altered downstream metabolites and metabolic pathways. Importantly, intrauterine supplementation with fructose 1,6-bisphosphate (F-1,6-BP), a direct product of PFKP catalysis, was able to rescue myocardial hypoplasia in fetal mice. Conversely, inhibiting glycolysis using 2-deoxyglucose (2-DG) reproduced the myocardial hypoplasia phenotype in both fetal mouse hearts and human embryonic stem-cell-derived cardiomyocytes (hESC-CMs). These findings establish PFKP as a critical regulator of glycolysis during embryonic cardiac development. They also provide novel insights suggesting that glycolytic defects or intrauterine hypoglycemia may represent common causes of myocardial hypoplasia. This research highlights potential applications for genetic interventions, prenatal screening, and targeted intrauterine therapeutic strategies.