Loss of function in the PLD1 gene causes congenital heart disease

A team of researchers co-led by Michael Frohman, MD, PhD, of Stony Brook University, has identified an important cause of congenital heart disease. They found that specific loss of function in the PLD1 gene (Phospholipase D1) causes right cardiac valve defects and neonatal cardiomyopathy. Their findings are outlined in a paper published early online in the Journal of Clinical Research.

Congenital heart disease is the most common type of birth defect, accounting for one-third of congenital anomalies with a worldwide incidence of seven per thousand births. Most of these defects include anomalies in valve formation. Right congenital heart disease involves dysfunction of the lung and tricuspid valves.

More than 25 years ago, Dr. Frohman’s laboratory recorded the PLD1 gene and has since studied its psychological function, as well as the potential for developing drugs that inhibit PLD1 activity. to treat thrombotic disorders and cancer. Their current research reveals that the loss of PLD1 function in a sensitive manner leads to congenital heart defects.

PLD1 is an enzyme that clears a specific lipid found in all cells to generate a signal that alters how cells behave when stimulated by hormones, neurotransmitters, and growth factors. Many research groups have been working over the last quarter of a century to explain how PLD1 helps cells to communicate with each other. “

Dr. Michael Frohman, Associate Research Fellow and Chair, Department of Pharmaceutical Sciences, School of Rehabilitation Medicine, Distinguished Professor, SUNY

He points out that congenital heart disease caused by loss of PLD1 function usually leads to malformation of the cardiac valves on the right side of the heart and sometimes the right ventricle. This inappropriate development of the heart sometimes prevents live birth, and in most other cases to date, the newborns would not survive without surgery or drug management.

The research on PLD1 and mutations associated with congenital heart disease involved 56 researchers worldwide, by lead author Najim Lahrouchi, MD, a physicist at the University of Amsterdam; and his consultant, Connie Bezzina, PhD, who co-directed the study with Dr. Frohman.

The team used whole-exome sequences in 2,718 cases of congenital heart disease and other procedures to identify 30 patients from 21 unrelated families of different ancestry with altered PLD1 genes on the two predominantly chromosomes. with congenital cardiac valve defects. The study also showed that inhibition of PLD1 reduces endothelial mesenchymal transitions, an established early stage in the initial development of valves at around the seventh week of pregnancy.

One of the mutations found in PLD1 is at a high enough level (2 percent) in Ashkenazi Jews that the mutation may have been implicated in prenatal genetic testing.

At Stony Brook, a graduate student in Frohman ‘s laboratory, Christian Salazar, assayed the PLD1 mutant proteins for action and found that almost all of them had lost biochemical activity as a result of the mutations.

Forrest Bowling, a graduate student in the Airola Laboratory in the Department of Biochemistry and Cell Biology, pointed out where the mutations are on the three-dimensional structure of PLD1. The structure, confirmed by Bowling and Michael Airola in collaboration with Dr. Frohman and Salazar, published in Natural Chemical Biology. The condition of the protein structure provided a detailed insight into why the mutations made the PLD1 enzyme inactive.

Overall, the study provides a greater understanding of the mechanisms of phenotypic disease and sensitivity associated with loss of PLD1 function, particularly in relation to congenital heart disease. Dr Frohman says future studies will focus on developing an understanding of the role of PLD1 in the development of heart valves and on the ongoing development of clinical facilities for families with or at risk of being affected. children.