3.2 Epistatic interaction between DES and PDE4DIPmutations
The remaining mutations were filtered as described in the methods to remove common variants and genes not expressed in the heart and performed segregation analyses of the remaining genes. This revealed a mutation in the PDE4DIP gene that segregated in all 4 affected family members with early onset heart block and AF. The PDE4DIPmutation (NM_001002811:c.367G>A) results in a non-conservative alanine to threonine substitution at amino acid 123 (p.A123T). The presence of PDE4DIP mutation in all family members with very early onset AF and heart block suggested an epistatic interaction with the DES gene, resulting in increased penetrance of these two traits. Another member of the family (II-6), who was found to be a carrier of the DES mutation had only developed late onset AF at age 60 but has neither NICM nor conduction disease (figure 1). One young unaffected 32-year-old member of the kindred who has been considered as too young to develop disease (III-5) was found to be a carrier of both mutations DES and PDE4DIP mutations and is being closely followed by a local cardiologist.
PDE4DIP is an anchoring protein that interacts with both phosphodiesterase 4D (PDE4D) and cAMP dependent protein kinase A (PKA) (Dodge et al., 2001) and several other proteins to form a multiprotein complex that plays an important role in targeting signaling processes to subcellular locations. PDE4D hydrolyzes cAMP and regulates its levels within cardiac myocytes where it also complexes with proteins mediating sympathetic signals to heart, including β-adrenergic receptors (Mongillo et al., 2004; Perry et al., 2002; Xiang et al., 2005).
A novel deleterious heterozygous variant of the ENG gene (NC_000009.11:g.130578055G>A) causing a p.A628V substitution also co-segregated with cardiomyopathy. The ENG gene encodes a membrane glycoprotein primarily expressed in the vascular endothelium and myocardium and has been previously identified as a modifier gene for hypertrophic cardiomyopathy (HCM) in patients with pathogenic MYH7 mutations, resulting in more profound myocardial fibrosis (Frustaci, Lanfranchi, Bellin, & Chimenti, 2012).