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.