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Cited by 27Congenital heart defects researchCardiomyopathy and Myosin StudiesCardiac electrophysiology and arrhythmias

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

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Edwards, Jonathan J., Rouillard, Andrew D., Fernandez, Nicolas F., Wang, Zichen, Lachmann, Alexander, Shankaran, Sunita S., Bisgrove, Brent W., Demarest, Bradley +18 more·2020·JACC: Basic to Translational Science
DOI 10.1016/j.jacbts.2020.01.012PMC PMC7188873
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Abstract

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 brk1, nckap1, and wasf2 and the regulators of small GTPase signaling cul3a and racgap1 are critical to cardiac development.

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  • A nonsense variant c.367C > T (p.Arg213Ter) in ABI1 was identified in a patient with cardiovascular dysfunction and neurodevelopmental disorder.

    “A nonsense variant, c.367C > T, p.Arg213Ter, in ABI1 was identified in a patient with cardiovascular dysfunction and NDD135–137 (Table 2v).”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [135]

    The Results (Gene set enrichment analyses; page unavailable) identify a nonsense ABI1 variant in a proband with a left-sided obstructive heart defect, but report it as p.R106X, not p.Arg213Ter. Our copy does not identify c.367C>T or say that this proband had a neurodevelopmental disorder. (LLM, conf=0.88)

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  1. [1]Razzaghi H. Oster M. Reefhuis J. Long-term outcomes in children with congenital heart disease: National Health Interview Survey J Pediatr 166 2015 119 124 25304924 PMC4378575
  2. [2]Pierpont M.E. Brueckner M. Chung W.K. Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart Association Circulation 138 2018 e653 e711 30571578 PMC6555769
  3. [3]Oyen N. Poulsen G. Wohlfahrt J. Boyd H.A. Jensen P.K. Melbye M. Recurrence of discordant congenital heart defects in families Circ Cardiovasc Genet 3 2010 122 128 20173214
  4. [4]Zaidi S. Choi M. Wakimoto H. De novo mutations in histone-modifying genes in congenital heart disease Nature 498 2013 220 223 23665959 PMC3706629
  5. [5]Benson D.W. Sharkey A. Fatkin D. Reduced penetrance, variable expressivity, and genetic heterogeneity of familial atrial septal defects Circulation 97 1998 2043 2048 9610535
  6. [6]Homsy J. Zaidi S. Shen Y. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies Science 350 2015 1262 1266 26785492 PMC4890146
  7. [7]Jin S.C. Homsy J. Zaidi S. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands Nat Genet 49 2017 1593 1601 28991257 PMC5675000
  8. [8]DePristo M.A. Banks E. Poplin R. A framework for variation discovery and genotyping using next-generation DNA sequencing data Nat Genet 43 2011 491 498 21478889 PMC3083463
  9. [9]Li H. Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform Bioinformatics 26 2010 589 595 20080505 PMC2828108
  10. [10]Bendl J. Musil M. Stourac J. Zendulka J. Damborsky J. Brezovsky J. PredictSNP2: a unified platform for accurately evaluating SNP effects by exploiting the different characteristics of variants in distinct genomic regions PLoS Comput Biol 12 2016 e1004962 PMC4880439 27224906
  11. [11]Kircher M. Witten D.M. Jain P. O'Roak B.J. Cooper G.M. Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants Nat Genet 46 2014 310 315 24487276 PMC3992975
  12. [12]Blake J.A. Bult C.J. Eppig J.T. Kadin J.A. Richardson J.E. Mouse Genome Database G The Mouse Genome Database: integration of and access to knowledge about the laboratory mouse Nucleic Acids Res 42 2014 D810 D817 24285300 PMC3964950
  13. [13]Pediatric Cardiac Genomics C Gelb B. Brueckner M. The Congenital Heart Disease Genetic Network Study: rationale, design, and early results Circ Res 112 2013 698 706 23410879 PMC3679175
  14. [14]Kuleshov M.V. Jones M.R. Rouillard A.D. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update Nucleic Acids Res 44 2016 W90 W97 27141961 PMC4987924
  15. [15]Liao Y. Wang J. Jaehnig E.J. Shi Z. Zhang B. WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs Nucleic Acids Res 47 2019 W199 W205 31114916 PMC6602449
  16. [16]Shankaran S.S. Dahlem T.J. Bisgrove B.W. Yost H.J. Tristani-Firouzi M. CRISPR/Cas9-Directed Gene Editing for the Generation of Loss-of-Function Mutants in High-Throughput Zebrafish F0 Screens Curr Protoc Mol Biol 119 2017 31.9.1 31.9.22 28678442 PMC7194136
  17. [17]Parant J.M. George S.A. Pryor R. Wittwer C.T. Yost H.J. A rapid and efficient method of genotyping zebrafish mutants Dev Dyn 238 2009 3168 3174 19890916 PMC3888828
  18. [18]Soderling S.H. Scott J.D. WAVE signalling: from biochemistry to biology Biochem Soc Trans 34 2006 73 76 16417486
  19. [19]Innocenti M. Zucconi A. Disanza A. Abi1 is essential for the formation and activation of a WAVE2 signalling complex Nat Cell Biol 6 2004 319 327 15048123
  20. [20]Li T. Kim A. Rosenbluh J. GeNets: a unified web platform for network-based genomic analyses Nat Methods 15 2018 543 546 29915188 PMC6450090
  21. [21]Richards A.A. Garg V. Genetics of congenital heart disease Curr Cardiol Rev 6 2010 91 97 21532774 PMC2892081
  22. [22]Leung C. Lu X. Liu M. Feng Q. Rac1 signaling is critical to cardiomyocyte polarity and embryonic heart development J Am Heart Assoc 3 2014 e001271 PMC4323834 25315346
  23. [23]Friedman J.M. Arbiser J. Epstein J.A. Cardiovascular disease in neurofibromatosis 1: report of the NF1 Cardiovascular Task Force Genet Med 4 2002 105 111 12180143
  24. [24]Martinelli S. Krumbach O.H.F. Pantaleoni F. Functional dysregulation of CDC42 causes diverse developmental phenotypes Am J Hum Genet 102 2018 309 320 29394990 PMC5985417
  25. [25]Liu Y. Wang J. Li J. Deletion of Cdc42 in embryonic cardiomyocytes results in right ventricle hypoplasia Clin Transl Med 6 2017 40 29101495 PMC5670094
  26. [26]Warga R.M. Wicklund A. Webster S.E. Kane D.A. Progressive loss of RacGAP1/ogre activity has sequential effects on cytokinesis and zebrafish development Dev Biol 418 2016 307 322 27339293
  27. [27]Singer J.D. Gurian-West M. Clurman B. Roberts J.M. Cullin-3 targets cyclin E for ubiquitination and controls S phase in mammalian cells Genes Dev 13 1999 2375 2387 10500095 PMC317026
  28. [28]Papizan J.B. Vidal A.H. Bezprozvannaya S. Bassel-Duby R. Olson E.N. Cullin-3-RING ubiquitin ligase activity is required for striated muscle function in mice J Biol Chem 293 2018 8802 8811 29653945 PMC5995497
  29. [29]Dubielecka P.M. Ladwein K.I. Xiong X. Essential role for Abi1 in embryonic survival and WAVE2 complex integrity Proc Natl Acad Sci U S A 108 2011 7022 7027 21482783 PMC3084068
  30. [30]Ring C. Ginsberg M.H. Haling J. Pendergast A.M. Abl-interactor-1 (Abi1) has a role in cardiovascular and placental development and is a binding partner of the alpha4 integrin Proc Natl Acad Sci U S A 108 2011 149 154 21173240 PMC3017183
  31. [31]Escobar B. de Carcer G. Fernandez-Miranda G. Brick1 is an essential regulator of actin cytoskeleton required for embryonic development and cell transformation Cancer Res 70 2010 9349 9359 20861187
  32. [34]Yan C. Martinez-Quiles N. Eden S. WAVE2 deficiency reveals distinct roles in embryogenesis and Rac-mediated actin-based motility EMBO J 22 2003 3602 3612 12853475 PMC165620
  33. [35]Yamazaki D. Suetsugu S. Miki H. WAVE2 is required for directed cell migration and cardiovascular development Nature 424 2003 452 456 12879075
  34. [36]Burggren W.W. Pinder A.W. Ontogeny of cardiovascular and respiratory physiology in lower vertebrates Annu Rev Physiol 53 1991 107 135 2042956
  35. [37]Miura G.I. Yelon D. A guide to analysis of cardiac phenotypes in the zebrafish embryo Methods Cell Biol 101 2011 161 180 21550443 PMC3292854
  36. [38]Li Y. Klena N.T. Gabriel G.C. Global genetic analysis in mice unveils central role for cilia in congenital heart disease Nature 521 2015 520 524 25807483 PMC4617540
  37. [39]Liu X. Yagi H. Saeed S. The complex genetics of hypoplastic left heart syndrome Nat Genet 49 2017 1152 1159 28530678 PMC5737968
  38. [40]King J.S. Veltman D.M. Georgiou M. Baum B. Insall R.H. SCAR/WAVE is activated at mitosis and drives myosin-independent cytokinesis J Cell Sci 123 2010 2246 2255 20530573 PMC2886745
  39. [41]Patel F.B. Bernadskaya Y.Y. Chen E. The WAVE/SCAR complex promotes polarized cell movements and actin enrichment in epithelia during C. elegans embryogenesis Dev Biol 324 2008 297 309 18938151 PMC2629559
  40. [42]Simons M. Mlodzik M. Planar cell polarity signaling: from fly development to human disease Annu Rev Genet 42 2008 517 540 18710302 PMC2814158
  41. [43]Henderson D.J. Chaudhry B. Getting to the heart of planar cell polarity signaling Birth Defects Res A Clin Mol Teratol 91 2011 460 467 21538810
  42. [44]Sinha T. Wang B. Evans S. Wynshaw-Boris A. Wang J. Disheveled mediated planar cell polarity signaling is required in the second heart field lineage for outflow tract morphogenesis Dev Biol 370 2012 135 144 22841628 PMC3432663
  43. [45]Wimuttisuk W. Singer J.D. The Cullin3 ubiquitin ligase functions as a Nedd8-bound heterodimer Mol Biol Cell 18 2007 899 909 17192413 PMC1805106
  44. [46]Cordero-Espinoza L. Hagen T. Regulation of Cullin-RING ubiquitin ligase 1 by Spliceosome-associated protein 130 (SAP130) Biol Open 2 2013 838 844 23951410 PMC3744076
  45. [47]Motta M. Fidan M. Bellacchio E. Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling Hum Mol Genet 28 2019 1007 1022 30481304
  46. [48]Steklov M. Pandolfi S. Baietti M.F. Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination Science 362 2018 1177 1182 30442762 PMC8058620
  47. [49]Suetsugu S. Kurisu S. Oikawa T. Yamazaki D. Oda A. Takenawa T. Optimization of WAVE2 complex-induced actin polymerization by membrane-bound IRSp53, PIP(3), and Rac J Cell Biol 173 2006 571 585 16702231 PMC2063866

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Authors
Edwards, J. J., Rouillard, A. D., Fernandez, N. F., Wang, Z., Lachmann, A., Shankaran, S. S., Bisgrove, B. W., Demarest, B., Turan, N., Srivastava, D., Bernstein, D., Deanfield, J., Giardini, A., Porter, G., Kim, R., Roberts, A. E., Newburger, J. W., Goldmuntz, E., Brueckner, M., Lifton, R. P., Seidman, C. E., Chung, W. K., Tristani-Firouzi, M., Yost, H. J., Ma’ayan, A., & Gelb, B. D.
Affiliations
  • Children's Hospital of Philadelphia (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Vanderbilt University (US)
  • University of Utah (US)
  • Coriell Institute For Medical Research (US)
  • Gladstone Institutes (US)
  • Stanford Medicine (US)
  • Great Ormond Street Hospital (GB)
  • University of Southern California (US)
  • Boston Children's Hospital (US)
  • University of Pennsylvania (US)
  • Yale University (US)
  • Howard Hughes Medical Institute (US)
  • Brigham and Women's Hospital (US)
  • Columbia University Irving Medical Center (US)
Corresponding author
Gelb, Bruce D.
ORCID
Venue
JACC: Basic to Translational Science
Publisher
Elsevier BV
Published
2020-04
Volume
5
Issue
4
Pages
376-386
ISSN
2452-302X (ISSN-L)
DOI
10.1016/j.jacbts.2020.01.012
PMC
PMC7188873
OpenAlex
W3015764232
Cited by
27
References
2
Citations by year
2026: 2 · 2025: 8 · 2024: 6 · 2023: 6 · 2022: 3 · 2021: 1 · 2020: 1
FWCI
0.88
Type
journal article
Language
en
Open access
Licence
Locations
  • JACC Basic to Translational Science (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
  • UCL Discovery (University College London) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health (5T32HL007915, 5U54HG006504, U01-HL098147, U01-HL098160, U01-HL098188, U01-HL098123, U01-HL098162, U01-HL098163)
  • Simons Foundation
  • Howard Hughes Medical Institute
  • National Center for Advancing Translational Sciences (U01 HL098153)
  • Johnson and Johnson
  • National Center for Research Resources
  • Roche
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
Keywords
congenital heart disease, left ventricular outflow tract obstruction, NCKAP1, RACGAP1, small GTPase signaling, de novo mutations, heart development, zebrafish knockdown

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