Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD.

Abstract

We studied 11 new kindreds with primary pigmented nodular adrenocortical disease (PPNAD) or Carney complex (CNC) and found that 82% of the kindreds had PRKAR1A gene defects (including seven novel inactivating mutations), most of which led to nonsense mRNA and, thus, were not expressed in patients' cells. However, a previously undescribed base substitution in intron 6 (exon 6 IVS +1G-->T) led to exon 6 skipping and an expressed shorter PRKAR1A protein. The mutant protein was present in patients' leukocytes and tumors, and in vitro studies indicated that the mutant PRKAR1A activated cAMP-dependent protein kinase A (PKA) signaling at the nuclear level. This is the first demonstration of an inactivating PRKAR1A mutation being expressed at the protein level and leading to stimulation of the PKA pathway in CNC patients. Along with the lack of allelic loss at the PRKAR1A locus in most of the tumors from this kindred, these data suggest that alteration of PRKAR1A function (not only its complete loss) is sufficient for augmenting PKA activity leading to tumorigenesis in tissues affected by CNC.

• Authors: Lionel Groussin, Lawrence S Kirschner, Caroline Vincent-Dejean, Karine Perlemoine, Eric Jullian, Brigitte Delemer, Sabina Zacharieva, Duarte Pignatelli, J Aidan Carney, Jean Pierre Luton, Xavier Bertagna, Constantine A Stratakis, Jérôme Bertherat
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 71 Issue 6 Pg. 1433-42 (Dec 2002) ISSN: 0002-9297 [Print] United States
• PMID: 12424709 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Codon, Initiator
• Protein Subunits
• RNA Splice Sites
• RNA, Messenger
• Cyclic AMP-Dependent Protein Kinases

Topics

• Adenocarcinoma (enzymology, genetics)
• Adrenal Gland Diseases (enzymology, genetics)
• Animals
• Base Sequence
• COS Cells
• Codon, Initiator (genetics)
• Cyclic AMP-Dependent Protein Kinases (genetics, metabolism)
• DNA Mutational Analysis
• Exons (genetics)
• Female
• Humans
• Introns (genetics)
• Leukocytes
• Loss of Heterozygosity
• Male
• Multiple Endocrine Neoplasia (enzymology, genetics)
• Mutation (genetics)
• Pancreatic Neoplasms (enzymology, genetics)
• Pedigree
• Promoter Regions, Genetic (genetics)
• Protein Subunits
• RNA Splice Sites (genetics)
• RNA, Messenger (genetics, metabolism)
• Signal Transduction
• Tumor Cells, Cultured