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Epistatic interaction of PDE4DIP and DES mutations in familial atrial fibrillation with slow conduction
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  • Maen Abou Ziki,
  • Neha Bhat,
  • Arpita Neogi,
  • Johny Abboud,
  • Salah Chouairi,
  • Tristan Driscoll,
  • Nelson Ugwu,
  • Ya Liu,
  • Emily Smith,
  • Martin Schwartz,
  • Joseph Akar ,
  • Arya Mani
Maen Abou Ziki
Yale University School of Medicine
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Neha Bhat
Yale School of Medicine
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Arpita Neogi
Yale School of Medicine
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Johny Abboud
Saint George Hospital University Medical Center
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Salah Chouairi
Saint George Hospital University Medical Center
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Tristan Driscoll
Yale School of Medicine
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Nelson Ugwu
Yale School of Medicine
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Ya Liu
Yale School of Medicine
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Emily Smith
Yale School of Medicine
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Martin Schwartz
Yale School of Medicine
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Joseph Akar
Yale University School of Medicine
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Arya Mani
Yale School of Medicine
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Abstract

Background: The genetic causes of atrial fibrillation (AF) with slow conduction are unknown. Methods: Eight kindreds with familial AF and slow conduction, including a family affected by early onset AF, heart block and incompletely penetrant non-ischemic cardiomyopathy (NICM) underwent whole exome sequencing. Results: A known pathogenic mutation in the desmin (DES) gene resulting in S13F substitution at a PKC phosphorylation site was identified in all four members of the kindred with early-onset AF and heart block, while only two developed NICM. Higher penetrance of the mutation for AF and heart block prompted the screening for DES modifier(s). A second deleterious mutation in the phosphodiesterase 4D interacting-protein (PDE4DIP) gene resulting in A123T substitution segregated with early onset AF, heart block and the DES mutation. Three additional novel deleterious PDE4DIP mutations were identified in four other unrelated kindreds. Characterization of PDE4DIPA123T in vitro suggested impaired compartmentalization of PKA and PDE4D characterized by reduced colocalization with PDE4D, increased cAMP activation leading to higher PKA phosphorylation of the β2-adrenergic-receptor, and decreased PKA phosphorylation of Desmin in response to isoproterenol stimulation compared to wildtype PDE4DIP. Conclusion: Our findings identify an epistatic interaction between DES and PDE4DIP variants, increasing the penetrance for conduction disease and arrhythmia.

Peer review status:IN REVISION

12 Jan 2021Submitted to Human Mutation
15 Jan 2021Assigned to Editor
15 Jan 2021Submission Checks Completed
19 Jan 2021Reviewer(s) Assigned
03 Mar 2021Review(s) Completed, Editorial Evaluation Pending
10 Mar 2021Editorial Decision: Revise Major
15 Jun 20211st Revision Received