Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects


Edwards JJ, Rouillard AD, Fernandez NF, Wang Z, Lachmann A, Shankaran SS, Bisgrove BW, Demarest B, Turan N, Srivastava D, Bernstein D, Deanfield J, Giardini A, Porter G, Kim R, Roberts AE, Newburger JW, Goldmuntz E, Brueckner M, Lifton RP, Seidman CE, Chung WK, Tristani-Firouzi M, Yost HJ, Ma’ayan A, Gelb BD.
JACC Basic Transl Sci. 2020 Apr 8;5(4):376-386. doi: 10.1016/j.jacbts.2020.01.012. eCollection 2020 Apr.
PMID: 32368696 Free PMC Article
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Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins brk1nckap1, and wasf2 and the regulators of small GTPase signaling cul3a and racgap1 are critical to cardiac development.



Figure 1 LVOTO Disease Gene Network Bipartite graph generated using GeNets Metanetwork v1.0 protein-protein interactions connecting left ventricular outflow tract obstruction (LVOTO) genes associated with enriched terms using either high fetal heart expression (HHE) in silico or Mouse Genome Informatics (MGI) library in silicofiltered genes and either Enrichr or WebGestalt. Of the genes associated with consistently enriched terms and not previously implicated in structural heart defects, CUL3 and RACGAP1 are the most strongly connected.

Figure 2 Crispr-Mediated Candidate Gene Knockdown in Zebrafish (A, C) Wild-type (WT), (C)cul3a, and (D)racgap1 knockout (KO) zebrafish at 2 days past fertilization. Reversed cardiac looping illustrated in cul3a KO as compared with WT, both on a cmlc2-GFP background. The racgap1 KO zebrafish demonstrate atrial dilation and pericardial edema. At = atria; CRISPR = clustered regularly interspaced short palindromic repeats; Ve = ventricle.