ArticleThe Journal of biological chemistry2015
Functional Characterization of PRKAR1A Mutations Reveals a Unique Molecular Mechanism Causing Acrodysostosis but Multiple Mechanisms Causing Carney Complex.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 37 citations in OpenAlex.
- PRKAR1A-related acrodysostosis with partial growth hormone deficiency: 18-month response to recombinant human growth hormone.Hormones (Athens, Greece) · 2026Review
- Acrodysostosis type 1: mechanisms explaining PRKAR1A mutation mediated dysregulation of cAMP-PKA signalling.Cell communication and signaling : CCS · 2026Review
- Conformational Dynamics and Allostery in the cAMP-Protein Kinase A Signalosome.Advances in experimental medicine and biology · 2026Review
- Recurrent Acrodysostosis-Related PKA RIα Mutant Reveals a Novel Mechanism of Aberrant PKA Deactivation.Journal of molecular biology · 2025Article
- Detection of PRKAR1A gene mutations in sporadic cardiac myxomas: a study of 24 cases.Virchows Archiv : an international journal of pathology · 2025Article
- Protein Kinase A in neurological disorders.Journal of neurodevelopmental disorders · 2024Review
- Phosphodiesterase 4D activity in acrodysostosis-associated neural pathology: too much or too little?Brain communications · 2024Review
- Growth patterns and outcomes of growth hormone therapy in patients with acrodysostosis.Journal of endocrinological investigation · 2023Article
- Recent advances in the molecular understanding of medulloblastoma.Cancer science · 2023Review
- The cAMP-signaling cancers: Clinically-divergent disorders with a common central pathway.Frontiers in endocrinology · 2022Review
- Yeast Two-Hybrid Screen Identifies PKA-Riα Interacting Proteins during Mouse Spermiogenesis.Genes · 2021Article
- GPharmacological reviews · 2021Review
- Noncanonical protein kinase A activation by oligomerization of regulatory subunits as revealed by inherited Carney complex mutations.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- The transcriptional landscape of Shh medulloblastoma.Nature communications · 2021Article
- Shortened Fingers and Toes: GNAS Abnormalities are Not the Only Cause.Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association · 2020Article
- Article
- Expanding the phenotypic spectrum of variants in PDE4D/PRKAR1A: from acrodysostosis to acroscyphodysplasia.European journal of human genetics : EJHG · 2018Article
- Switching Cyclic Nucleotide-Selective Activation of Cyclic Adenosine Monophosphate-Dependent Protein Kinase Holoenzyme Reveals Distinct Roles of Tandem Cyclic Nucleotide-Binding Domains.ACS chemical biology · 2017Article
- Channeling of cAMP in PDE-PKA Complexes Promotes Signal Adaptation.Biophysical journal · 2017Article
- Article
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Authors and funding
9 authors at 7 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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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