Evaluating Cardiac Gene Expression in Maternal Phenylketonuria Offspring

Maternal phenylketonuria (MPKU) is a teratogenic syndrome, caused by development of offspring in a uterine environment made toxic by the metabolic imbalance of PKU. The birth defects resulting from untreated MPKU include microcephaly with concomitant mental retardation, growth retardation, and congenital heart defects. Congenital heart defects have been identified and characterized in MPKU offspring, using the BTBR-PAH mouse MPKU model. Subsequently, this mouse model was used to start investigating the molecular basis of MPKU congenital heart defects. It was determined that three genes involved in heart contractility and development were significantly downregulated in MPKU fetal hearts at 18.5 days postcoitum, compared to non-PKU control offspring. These three genes were troponin T2 (Tnnt2), troponin I3 (Tnni3), and ryanodine receptor 2 (Ryr2). We used the BTBR-PAH mouse model to further evaluate the relationship between maternal hyperphenylalaninemia and cardiac gene expression in MPKU fetal hearts. It was hypothesized that an association exists between maternal blood phenylalanine (Phe) levels and expression levels of certain cardiac genes. More specifically, our alternate hypothesis stated that elevated maternal blood Phe levels are associated with decreased expression of Tnnt2, Tnni3, and Ryr2 in MPKU fetal hearts. Relative quantification of Tnnt2, Tnni3, and Ryr2 transcript abundance in MPKU fetal hearts was performed using real-time PCR. Linear regression analysis was then performed on relative Tnnt2, Tnni3, and Ryr2 transcript levels as a function of maternal blood Phe concentration. The regression analyses for all three genes were found to be nonsignificant. Therefore, we were unable to reject the null hypothesis, which stated that