Mutations and polymorphisms in the gene encoding regulatory subunit type 1-alpha of protein kinase A (PRKAR1A): an update.
PRKAR1A encodes the regulatory subunit type 1-alpha (RIalpha) 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 RIalpha haploinsufficiency and, as a result, activated cAMP signaling. Recently, it became apparent that CNC may be caused not only by RIalpha haploinsufficiency, but also by the expression of altered RIalpha protein, as proven by analysis of expressed mutations in the gene, consisting of amino acid 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.
Horvath
Anélia
A
Section on Endocrinology and Genetics, Program in Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Bertherat
Jérôme
J
Groussin
Lionel
L
Guillaud-Bataille
Marine
M
Tsang
Kitman
K
Cazabat
Laure
L
Libé
Rosella
R
Remmers
Elaine
E
René-Corail
Fernande
F
Faucz
Fabio Rueda
FR
Clauser
Eric
E
Calender
Alain
A
Bertagna
Xavier
X
Carney
J Aidan
JA
Stratakis
Constantine A
CA
D017398:Alternative Splicing / Q000235:genetics; D056733:Carney Complex / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics*; D016368:Frameshift Mutation / Q000235:genetics; D056726:Genetic Association Studies; D006801:Humans; D009154:Mutation / Q000235:genetics*; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human