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

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.

Regulation of cardiac function by cAMP nanodomains

“…Both MyBPC and TnI interact with myomegalin (also called PDE4DIP), an AKAP involved in the control of MyBPC and TnI phosphorylation [ 104 ]. The exact localization and constitution of the domain associated with PDE4DIP is unclear, although mutations in PDE4DIP are known to impair cAMP signaling at the myofilament giving rise to arrhythmias [ 105 ].…”

“…A123T mutations in PDE4DIP are associated with early-onset atrial fibrillation and heart block, which appears to be induced by impairment of PKA and PDE4D compartmentation, resulting in increased cAMP near the β2AR site and decreased PKA phosphorylation of desmin [ 105 ]. The TnT R173W mutation presents with impaired cardiomyocyte contractility due to disrupted interactions between troponin and tropomyosin, and reduced PKA binding to sarcomere domains, causing TnI hypophosphorylation in DCM [ 115 ].…”

Whole-genome sequencing of ethnolinguistic diverse northwestern Chinese Hexi Corridor people from the 10K_CPGDP project suggested the differentiated East-West genetic admixture along the Silk Road and their biological adaptations

“…Recent large-scale genomic projects mainly focused on Europeans, which may cause European bias in human genetic research and introduce health inequality in the precision medicine era, such as the Genome Aggregation Database (gnomAD) (Collins, et al 2020), Trans-Omics for Precision Medicine (TOPMed) program (Taliun, et al 2021) and UK Biobank (Halldorsson, et al 2022). However, high-coverage whole-genome sequencing studies in East Asian populations have so far mainly focused on demographically larger Han populations (Jeon, et al 2020; Ma, Yang, et al 2021; Zhang, Luo, et al 2021) or been targeted at specific metabolic diseases (Cao, et al 2020). The underrepresentation of ethnolinguistically diverse East Asians impedes our complete understanding of modern humans’ evolutionary history, genetic discovery, and human health.…”

“…Northwest China, including the provinces of Gansu, Qinghai, and Shaanxi and the autonomous regions of Xinjiang and Ningxia, borders the countries of Central Asia, South Asia, Russia, and Mongolia and is located at the junction between the Eurasian steppes and the Central Plains of China. This area, now widely inhabited by Sinitic, Tibeto-Burman (TB), Mongolic (MG), and Turkic (TK)-speaking ethnic groups, is a strategic location for genetic and cross-cultural communications between West Eurasia and inland China in prehistoric and historical periods (Xu, et al 2008; Feng, et al 2017; Ning, et al 2019; Ma, Yang, et al 2021). Additionally, Northwest China connected lowland East Asia and the highland Tibetan Plateau and served as the vital buffer area for ancient people to settle on the Qinghai-Tibet Plateau (Ding, et al 2020).…”

Hemodynamic stress‐induced cardiac remodelling is not modulated by ablation of phosphodiesterase 4D interacting protein

“…Therefore, it is not surprising that Pde4dip mutations are associated with familial dilated cardiomyopathy and arrhythmia. 24 , 25 , 26 However, the precise role of PDE4DIP in response to pathological stress in vivo remains unknown.…”