Mutations causing acrodysostosis-2 facilitate activation of phosphodiesterase 4D3

Abstract

Type 2 acrodysostosis (ACRDYS2), a rare developmental skeletal dysplasia characterized by short stature, severe brachydactyly and facial dysostosis, is caused by mutations in the phosphodiesterase (PDE) 4D (PDE4D) gene. Several arguments suggest that the mutations should result in inappropriately increased PDE4D activity, however, no direct evidence supporting this hypothesis has been presented, and the functional consequences of the mutations remain unclear. We evaluated the impact of four different PDE4D mutations causing ACRDYS2 located in different functional domains on the activity of PDE4D3 expressed in Chinese hamster ovary cells. Three independent approaches were used: the direct measurement of PDE activity in cell lysates, the evaluation of intracellular cAMP levels using an EPAC-based (exchange factor directly activated by cAMP) bioluminescence resonance energy transfer sensor , and the assessment of PDE4D3 activation based on electrophoretic mobility. Our findings indicate that PDE4D3s carrying the ACRDYS2 mutations are more easily activated by protein kinase A-induced phosphorylation than WT PDE4D3. This occurs over a wide range of intracellular cAMP concentrations, including basal conditions, and result in increased hydrolytic activity. Our results provide new information concerning the mechanism whereby the mutations identified in the ACRDYS2 dysregulate PDE4D activity, and give insights into rare diseases involving the cAMP signaling pathway. These findings may offer new perspectives into the selection of specific PDE inhibitors and possible therapeutic intervention for these patients.

Understanding PDE4's function in Alzheimer's disease; a target for novel therapeutic approaches

“…Once again, recovery of low cAMP concentrations and attenuated CREB signaling was crucial in the gain of function resulting from PDE4D longform ablation. In further support for the concept that reduced PDE4D activity facilitates cognition and memory formation, genetic mutations in the human PDE4D gene that cause acrodysostosis [42–44] lead to an activation of PDE4D longform enzymes (via PKA phosphorylation) [45] that inhibits CREB activity [46] and promotes intellectual disability [47].…”

Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: inhibition and beyond

“…With regard to compartment-specific changes in cAMP signaling, studies examining brain tissue from patients with bipolar disorder show no change in membrane but increased signaling in the cytosol, which is normalized by the classic mood stabilizer lithium (27)(28)(29)(30)(31)(32). Other disease states where compartment-specific defects in cyclic nucleotide signaling have been noted include-but are not limited to-erectile dysfunction (33), hypertension (34), cardiac hypertrophy (25,35), acrodysostosis (36)(37)(38)(39), and Huntington's disease (40,41).…”

Shortened Fingers and Toes: GNAS Abnormalities are Not the Only Cause

“…1; orange text and symbols). The location and functional analysis of PDE4D mutations occurring in ACRDYS2 indicate that these mutations can influence the regulation of PDE activity by PKA resulting in increased hydrolytic activity [61,62]. Increased expression of other PDE4 isoforms may also occur, as suggested by observations in some patients [58].…”