Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy
Najim Lahrouchi, … , Michael A. Frohman, Connie R. Bezzina
Najim Lahrouchi, … , Michael A. Frohman, Connie R. Bezzina
Published March 1, 2021
Citation Information: J Clin Invest. 2021;131(5):e142148. https://doi.org/10.1172/JCI142148.
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Research Article Cardiology Genetics

Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy

Abstract

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.

Authors

Najim Lahrouchi, Alex V. Postma, Christian M. Salazar, Daniel M. De Laughter, Fleur Tjong, Lenka Piherová, Forrest Z. Bowling, Dominic Zimmerman, Elisabeth M. Lodder, Asaf Ta-Shma, Zeev Perles, Leander Beekman, Aho Ilgun, Quinn Gunst, Mariam Hababa, Doris Škorić-Milosavljević, Viktor Stránecký, Viktor Tomek, Peter de Knijff, Rick de Leeuw, Jamille Y. Robinson, Sabrina C. Burn, Hiba Mustafa, Matthew Ambrose, Timothy Moss, Jennifer Jacober, Dmitriy M. Niyazov, Barry Wolf, Katherine H. Kim, Sara Cherny, Andreas Rousounides, Aphrodite Aristidou-Kallika, George Tanteles, Bruel Ange-Line, Anne-Sophie Denommé-Pichon, Christine Francannet, Damara Ortiz, Monique C. Haak, Arend D.J. Ten Harkel, Gwendolyn T.R. Manten, Annemiek C. Dutman, Katelijne Bouman, Monia Magliozzi, Francesca Clementina Radio, Gijs W.E. Santen, Johanna C. Herkert, H. Alex Brown, Orly Elpeleg, Maurice J.B. van den Hoff, Barbara Mulder, Michael V. Airola, Stanislav Kmoch, Joey V. Barnett, Sally-Ann Clur, Michael A. Frohman, Connie R. Bezzina

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Figure 2

Activity of pathogenic PLD1 variants and their placement on the 3D protein structure.

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Activity of pathogenic PLD1 variants and their placement on the 3D prote...
(A) Activity of missense PLD1 variants above the K898R negative control as normalized to the WT PLD1 positive control. Data points represent independent experiments performed in duplicate and averaged. Error bars represent the SEM. Magenta, N-terminus; blue, PH-domain; yellow, catalytic domain; green, C-terminus N-term, N-terminus; C-term, C-terminus. (B) Placement of missense variants on the PLD1 catalytic domain crystal structure. α Helices are shown in cyan, and β strands are shown in magenta. Spheres indicate pathogenic missense mutations: green spheres indicate active site variants; orange spheres indicate PI(4,5)P2–binding (PIP2-binding) mutants; and blue spheres indicate structural mutants. Insets show close-ups of WT residue interactions potentially disrupted by pathogenic variants. Pathogenic residues are represented by yellow sticks; black dashed lines indicate hydrogen bonds; and green dashed lines indicate cation-pi interaction. See Supplemental Videos 7–24 for rotatable presentations and a depiction of the impact of mutations on local structure.