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 (RIa) 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 RIa haploinsufficiency and, as a result, activated cAMP signaling. Recently, it became apparent that CNC may be caused not only by RIa haploinsufficiency, but also by the expression of altered RIa 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 0 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,

Screening of PRKAR1A and PDE4D in a Large Italian Series of Patients Clinically Diagnosed With Albright Hereditary Osteodystrophy and/or Pseudohypoparathyroidism

“…(13,16,pt A1) We also cross-referenced mutations associated with ACRDYS with those associated to Carney Complex, and we did not find any molecular overlap, suggesting that different substitutions lead to different and opposite effects on protein function, with consequent different clinical phenotypes. (24) PDE4D genetic defects in our series…”

17q24.2 microdeletions: a new syndromal entity with intellectual disability, truncal obesity, mood swings and hallucinations

“…160980). [30][31][32] This complex is characterized by pigmented lesions of the skin and mucosae, myxomas, endocrine tumors or overactivity and schwannomas. The patient of Blyth et al 13 was reported with Carney Complex Plus syndrome, indicating that not all her phenotypic characteristics could be explained by Carney Complex.…”

Newly Diagnosed Carney Complex in 3 Young Adults with Primary Adrenal Cushing Syndrome – A Case Series and Review of the Literature

“…The variant p.E257K (c.769G>A; g.114278G>A; NM_002734) was identified in case A, and the intronic variant g.101770A>G (NM_002734), that is predicted to abolish an acceptor splice site, was identified in case C. Both mutations have been previously associated with CNC (8,9).…”