Epistatic interaction of PDE4DIP and DES mutations in familial atrial fibrillation with slow conduction

Hum Mutat. 2021 Oct;42(10):1279-1293. doi: 10.1002/humu.24265. Epub 2021 Jul 29.

Abstract

The genetic causes of atrial fibrillation (AF) with slow conduction are unknown. Eight kindreds with familial AF and slow conduction, including a family affected by early-onset AF, heart block, and incompletely penetrant nonischemic dilated cardiomyopathy (DCM) underwent whole exome sequencing. A known pathogenic mutation in the desmin (DES) gene resulting in p.S13F substitution (NM_001927.3:c.38C>T) 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 DCM. Higher penetrance for AF and heart block prompted a genetic screening for DES modifier(s). A deleterious mutation in the phosphodiesterase-4D-interacting-protein (PDE4DIP) gene resulting in p.A123T substitution (NM_001002811:c.367G>A) was identified that 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 after isoproterenol stimulation. Our findings identify PDE4DIP as a novel gene for slow AF and unravel its epistatic interaction with DES mutations in development of conduction disease and arrhythmia.

Keywords: DES; ENG; PDE4DIP; cardiomyopathy; desmin; early-onset atrial fibrillation; heart block; myomegalin; slow conduction; slow ventricular response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Atrial Fibrillation* / genetics
  • Cardiomyopathy, Dilated* / genetics
  • Cytoskeletal Proteins / genetics*
  • Desmin / genetics*
  • Exome Sequencing
  • Humans
  • Mutation
  • Penetrance

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytoskeletal Proteins
  • Desmin
  • PDE4DIP protein, human