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In vitro functional studies of naturally occurring pathogenic PRKAR1A mutations that are not subject to nonsense mRNA decay
Author(s) -
Greene Elizabeth L.,
Horvath Anelia D.,
Nesterova Maria,
Giatzakis Christoforos,
Bossis Ioannis,
Stratakis Constantine A.
Publication year - 2008
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20688
Subject(s) - nonsense mediated decay , biology , nonsense , genetics , nonsense mutation , messenger rna , subject (documents) , in vitro , mutation , gene , rna , rna splicing , missense mutation , library science , computer science
Patients presenting with primary pigmented nodular adrenocortical disease (PPNAD), Carney complex (CNC), or sporadic tumors were previously found to carry germline mutations in the human type Iα regulatory subunit (RIα) of adenosine 3′,5′‐cyclic monophosphate (cyclic AMP [cAMP])‐dependent protein kinase (PKA; PRKAR1A). Although about 90% of disease‐causing PRKAR1A mutations lead to premature stop codon generation and subsequent degradation of the mutant message by nonsense‐mediated mRNA decay (NMD), here we describe seven PRKAR1A mutations whose mRNAs do not seem to undergo NMD and instead result in an expressed mutant RIα protein. The expressed mutations (p.Ser9Asn, p.Glu60_Lys116del [Δ‐exon 3], p.Arg74Cys, p.Arg146Ser, p.Asp183Tyr, p.Ala213Asp, and p.Gly289Trp) were spread over all the functional RIα domains, and all of them exhibited increased PKA activity, which we attribute to decreased binding to cAMP and/or the catalytic subunit. Our data further corroborate the previous finding that altered PRKAR1A function, not only haploinsufficiency, is enough to elevate PKA activity which is apparently associated with tumorigenesis in tissues affected by CNC. In some cases, as with the Δ‐exon 3 mutation, we may even conclude that the presence of a mutant PRKAR1A protein may be more harmful than allelic loss. Hum Mutat 29(5), 633–639, 2008. Published 2008, Wiley‐Liss, Inc.