ESPE Abstracts

Background: In humans, activating mutations in the PRKAR1A gene cause acrodysostosis1 (ACRDYS1). Two striking features of this rare developmental and skeletal disorder are renal resistance to PTH and chondrodysplasia resulting from the constitutive inhibition of PTHR1/Gsa/AC/cAMP/PKA signaling caused by the PRKAR1A mutations.

Objective and hypotheses: Document the consequences of the germline expression of a PRKAR1A mutation causing a dominant repression of cAMP-dependent PKA.

Method: Develop a mouse knock-in of the recurrent acrodysostosis R368X PRKAR1A mutation.

Results: No litters, thus no homozygous [R368X]/[R368X] mice, were obtained from [R368X]/[+] females. In [R368X]/[+] mice born from [R368X]/[+] males crossed to WT females, western blots analysis confirmed mutant allele heterozygous expression. Growth retardation, peripheral acrodysostosis (including brachydactyly affecting all digits) and facial dysostosis were demonstrated in [R368X]/[+] mice by weight curves and skeletal measurements (micro CT scan) as a function of time. [R368X]/[+] male and female mice were similarly affected. Unexpected, postnatal cartilage (alcian blue) and bone (alizarin red) analysis revealed a striking delay in mineralization of the cartilage and epiphyseal secondary ossification centers in mutant mice. Plasma PTH and basal urinary cAMP were significantly higher in [R368X]/[+] compared to WT mice. PTH injection increased urinary cAMP similarly in [R368X]/[+] and WT mice. PKA catalytic PRKACA subunit expression was regulated in a tissue (kidney not bone and liver) and subunit (not the regulatory PRKAR2A and PRKAR2B) manner.

Conclusion: This model, the first describing germline expression of a PRKAR1A mutation causing dominant repression of cAMP-dependent PKA, reproduces the main features of ACRDYS1 in humans. It should be helpful to decipher the specificity of the cAMP/PKA signaling pathway, a pathway playing a crucial transduction role for numerous stimuli. In addition, our results raise the possibility that PRKAR1A is a molecular hub at the crossroads of signaling pathways orchestrating chondrocyte proliferation and differentiation.