title: Mutations and polymorphisms in the gene encoding regulatory subunit type 1-alpha of protein kinase A (PRKAR1A): an update.
abstract: 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.
authors.affiliation: 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.
authors.forename: Anélia
authors.initials: A
authors.lastname: Horvath
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Lionel
authors.initials: L
authors.lastname: Groussin
authors.forename: Marine
authors.initials: M
authors.lastname: Guillaud-Bataille
authors.forename: Kitman
authors.initials: K
authors.lastname: Tsang
authors.forename: Laure
authors.initials: L
authors.lastname: Cazabat
authors.forename: Rosella
authors.initials: R
authors.lastname: Libé
authors.forename: Elaine
authors.initials: E
authors.lastname: Remmers
authors.forename: Fernande
authors.initials: F
authors.lastname: René-Corail
authors.forename: Fabio Rueda
authors.initials: FR
authors.lastname: Faucz
authors.forename: Eric
authors.initials: E
authors.lastname: Clauser
authors.forename: Alain
authors.initials: A
authors.lastname: Calender
authors.forename: Xavier
authors.initials: X
authors.lastname: Bertagna
authors.forename: J Aidan
authors.initials: JA
authors.lastname: Carney
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: 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
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human