Bone Abstracts

Acrodysostosis refers to a group of rare chondrodysplasia that share severe brachydactyly, short stature and nasal hypoplasia. Through a candidate gene approach or exome sequencing, heterozygous mutations in PRKAR1A or in PDE4D, respectively, have been identified in patients with acrodysostosis. PRKAR1A encodes the regulatory subunit of the protein kinase A (PKA), which allows, upon binding of cAMP, phosphorylation of target proteins by the catalytic subunit of PKA. PDE4D is a cAMP-specific phosphodiesterase. Interestingly, patients with PRKAR1A mutations present with resistance to hormones that signal through G-protein coupled receptors including PTH, TSH and epinephrine resistance. PDE4D mutations have been identified in patients with acrodysostosis yet, in most patients, no hormone resistance. In addition, impaired cognitive function is more prevalent in patients with acrodysostosis due to PDE4D mutations. We propose that acrodysostosis results from the deficient action of PTHrp, hence PKA, because the chondrodysplasia is highly reminiscent of bone features observed in patients with mutations in PTHLH, the gene encoding PTHrp and PHP1A/pseudoPHP syndromes caused by inactivating loss of function mutation in Gsa, the α subunit of the G-protein necessary for the signaling of GPCRs. Our in vitro studies indicate that PRKAR1A mutants are expressed when transfected in a cell model, and prevent the dissociation of the catalytic subunit of PKA. The impact of the PDE4D mutations on the protein function remains unsolved. Further investigation of the growth pattern, chondrodysplasia and hormone resistance in patients with acrodysostosis is required to decipher the roles of key components of the cAMP pathway in endocrine diseases.