The Pleiotropic Effect of a Deleterious DES Mutation in Familial Atrial Fibrillation and the Role of PDE4DIP As a Genetic Modifier for Heart Block

Abstract Background Atrial fibrillation (AF) is a common cardiac arrhythmia and is a major cause of ischemic stroke. It is a heritable disease, which is occasionally transmitted with an autosomal dominant pattern of inheritance. Methods We recruited a three-generation Lebanese kindred with five living family members affected by early onset familial AF (in early 30 years of age) with and without heart block and cardiomyopathy. Affected and unaffected family members underwent whole exome sequencing (WES). Two additional members of the family with undefined arrhythmias, heart block and pacemaker implantation had died from non-ischemic cardiomyopathy (NICM). Results A pathogenic mutation in the DES gene resulting in a serine to phenylalanine substitution at codon 13 in the Desmin protein segregated with early-onset AF. Four of the five patients had heart block and only two developed NICM later in life. Desmin, an intermediate filament protein, plays a pivotal role in the electromechanical functioning of cardiomyocytes and mutations in the DES gene have been implicated in skeletal myopathies, dilated cardiomyopathies and cardiac conduction disease. These mutations exhibit often incomplete penetrance and pleiotropic effects, but modifier genes that explain this behavior have not been identified. Analysis of WES data identified twelve shared variants predicted as damaging by both PolyPhen2 or SIFT software segregated with both early onset AF and heart block among DES mutation carriers. After filtering for known disease genes and genes not expressed in the heart, a rare novel non-conservative mutation in phosphodiesterase 4 D interacting protein (PDE4DIP) gene was identified that perfectly segregated with both heart block and AF. The mutation results in a non-conservative substitution of alanine at codon 123 for threonine. In-silico analysis predicted creation of a putative MAPK phosphorylation site. Functional in vitro characterization of the PDE4DIP p.A123T substitution showed increased cAMP levels by FRET sensor imaging in response to isoproterenol stimulation compared to wildtype transfected cells. cAMP mediates the catecholaminergic control of cardiac conduction and contractility. The PDE4DIP protein anchors PDE4D to the Golgi/centrosomal area in the sarcomeres of the myocardium and skeletal muscle and plays a critical role in subcellular partitioning of the cAMP signal and its dependent pathways. Surprisingly, there was decreased beta-adrenergic receptor phosphorylation in the mutant cells, suggesting reduced membrane PKA activity, possibly due to mislocalization of PDE4D. Inactivation of PDE4D has been linked to cardiomyopathy and arrhythmias including AF. Interestingly, genome-wide association studies have linked both PDE4D and PDE4DIP to ischemic stroke. Conclusion Our findings establish early onset AF as a presenting phenotype for DES mutations and identifies PDE4DIP as a modifier gene for its role in the development of conduction disease. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): National Institutes of Health, USA