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).