Mechanisms underlying skeletal and neural birth defect caused by mutations in phosphodiesterase-4D

What is it about?

Mutations in the phosphodiesterase 4D, that regulates availability of the secondary messenger cyclic adenosine monophosphate (cAMP), cause a rare disease presenting skeletal defects as well as intellectual disability in most cases. The net effect of the mutations is reduced cAMP signalling, but the molecular mechanisms leading to this are poorly understood. It has been suggested that mutated PDE4D has increased activity leading to reduced signalling. Here we propose novel mechanisms including: • Mutated PDE4D altered localisation affects strict coordination of its activity reducing signalling. • Reduced dimerization of mutated PDE4D increases the proportion of the monomeric form leading to reduced signalling.

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Why is it important?

Better understanding the disease mechanisms is crucial to developing properly targeted effective therapeutic approaches.