Key result
PRKAR1A mutations causing acrodysostosis impair cAMP binding and reduce PKA activation, whereas homologous mutations causing Carney complex express additional defects like accelerated protein degradation.
The study identifies that while both acrodysostosis and Carney complex mutations in PRKAR1A cause cAMP resistance, Carney complex mutations uniquely lead to accelerated protein degradation and constitutive PKA activation.
Distinguishes mutation-specific PRKAR1A defects across syndromes; extends mechanistic insights but leaves open clinical translation.
The main target of cAMP is PKA, the main regulatory subunit of which (PRKAR1A) presents mutations in two genetic disorders: acrodysostosis and Carney complex. In addition to the initial recurrent mutation (R368X) of the PRKAR1A gene, several missense and nonsense mutations have been observed recently in acrodysostosis with hormonal resistance. These mutations are located in one of the two cAMP-binding domains of the protein, and their functional characterization is presented here. Expression of each of the PRKAR1A mutants results in a reduction of forskolin-induced PKA activation (measured by a reporter assay) and an impaired ability of cAMP to dissociate PRKAR1A from the catalytic PKA subunits by BRET assay. Modeling studies and sensitivity to cAMP analogs specific for domain A (8-piperidinoadenosine 3',5'-cyclic monophosphate) or domain B (8-(6-aminohexyl)aminoadenosine-3',5'-cyclic monophosphate) indicate that the mutations impair cAMP binding locally in the domain containing the mutation. Interestingly, two of these mutations affect amino acids for which alternative amino acid substitutions have been reported to cause the Carney complex phenotype. To decipher the molecular mechanism through which homologous substitutions can produce such strikingly different clinical phenotypes, we studied these mutations using the same approaches. Interestingly, the Carney mutants also demonstrated resistance to cAMP, but they expressed additional functional defects, including accelerated PRKAR1A protein degradation. These data demonstrate that a cAMP binding defect is the common molecular mechanism for resistance of PKA activation in acrodysosotosis and that several distinct mechanisms lead to constitutive PKA activation in Carney complex.
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Rhayem et al. (2015) studied Acrodysostosis and Carney complex. PRKAR1A mutations was evaluated on PKA activation and cAMP binding ability. PRKAR1A mutations causing acrodysostosis impair cAMP binding and reduce PKA activation, whereas homologous mutations causing Carney complex express additional defects like accelerated protein degradation.
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