This article is a US Government work, and, as such, is in the public domain in the United States of America.
Article first published online: 26 MAR 2010
This article is a US Government work, and, as such, is in the public domain in the United States of America. Published in 2010 by Wiley-Liss, Inc.
Volume 31, Issue 4, pages 369–379, April 2010
How to Cite
Horvath, A., Bertherat, J., Groussin, L., Guillaud-Bataille, M., Tsang, K., Cazabat, L., Libé, R., Remmers, E., René-Corail, F., Faucz, F. R., Clauser, E., Calender, A., Bertagna, X., Carney, J. A. and Stratakis, C. A. (2010), Mutations and polymorphisms in the gene encoding regulatory subunit type 1-alpha of protein kinase A (PRKAR1A): an update. Hum. Mutat., 31: 369–379. doi: 10.1002/humu.21178
Communicated by Jurgen Horst
- Issue published online: 26 MAR 2010
- Article first published online: 26 MAR 2010
- Manuscript Accepted: 8 NOV 2009
- Manuscript Received: 1 SEP 2009
- Carney complex;
PRKAR1A encodes the regulatory subunit type 1-alpha (RIα) of the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA). Inactivating PRKAR1A mutations are known to be responsible for the multiple neoplasia and lentiginosis syndrome Carney complex (CNC). To date, at least 117 pathogenic variants in PRKAR1A have been identified (online database: http://prkar1a.nichd.nih.gov). The majority are subject to nonsense mediated mRNA decay (NMD), leading to RIα haploinsufficiency and, as a result, activated cAMP signaling. Recently, it became apparent that CNC may be caused not only by RIα haploinsufficiency, but also by the expression of altered RIα protein, as proven by analysis of expressed mutations in the gene, consisting of aminoacid substitutions and in-frame genetic alterations. In addition, a new subgroup of mutations that potentially escape NMD and result in CNC through altered (rather than missing) protein has been analyzed—these are frame-shifts in the 3′ end of the coding sequence that shift the stop codon downstream of the normal one. The mutation detection rate in CNC patients is recently estimated at above 60%; PRKAR1A mutation-negative CNC patients are characterized by significant phenotypic heterogeneity. In this report, we present a comprehensive analysis of all presently known PRKAR1A sequence variations and discuss their molecular context and clinical phenotype. Hum Mutat 31:369–379, 2010. Published 2010 Wiley-Liss, Inc.