Molecular Analysis of the Cyclic AMP-Dependent Protein Kinase A (PKA) Regulatory Subunit 1A (PRKAR1A
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- 作者：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 ; Jé ; rô ; me Bertherat
- 刊名：The American Journal of Human Genetics
- 出版年：2002
- 出版时间：December 2002
- 年：2002
- 卷：71
- 期：6
- 页码：1433-1442
- 全文大小：913 K
文摘
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.