Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex

Abstract

Carney complex (CNC) is an autosomal dominant multiple neoplasia syndrome, which has been linked to loci on 2p16 and 17q22-24. We recently reported that PRKAR1A, which codes for the type 1A regulatory subunit of protein kinase A (PKA), is a tumor suppressor gene on chromosome 17 that is mutated in some CNC families. To evaluate the spectrum of PRKAR1A mutations, we identified its genomic structure and screened for mutations in 54 CNC kindreds (34 families and 20 patients with sporadic disease). Fourteen families were informative for linkage analysis: four of four families that mapped to 17q had PRKAR1A mutations, whereas there were no mutations found in seven families exhibiting at least one recombination with 17q. In six of the latter, CNC mapped to 2p16. PRKAR1A mutations were also found in 12 of 20 non-informative families and 7 of 20 sporadic cases. Altogether, 15 distinct PRKAR1A mutations were identified in 22 of 54 kindreds (40.7%). In 14 mutations, the sequence change was predicted to lead to a premature stop codon; one altered the initiator ATG codon. Mutant mRNAs containing a premature stop codon were unstable, as a result of nonsense-mediated mRNA decay. Accordingly, the predicted truncated PRKAR1A protein products were absent in these cells. We conclude that (i) genetic heterogeneity exists in CNC; and (ii) all of the CNC alleles on 17q are functionally null mutations of PRKAR1A. CNC is the first human disease recognized to be caused by mutations of the PKA holoenzyme, a critical component of cellular signaling.

Identification of a clinically homogenous subgroup of benign cortisol-secreting adrenocortical tumors characterized by alterations of the protein kinase A (PKA) subunits and high PKA activity.

“…Various components of this pathway have been implicated in adrenocortical tumorigenesis, including the adrenocorticotropin (ACTH) receptor, the Gas subunit of Gs protein, the PKA regulatory subunit type 1 A (PRKAR1A), and more recently the phosphodiesterase PDE11A (4)(5)(6)(7)(8)(9). The PRKAR1A gene was found to be responsible for most cases of primary pigmented adrenocortical disease (PPNAD), a rare cause of ACTHindependent Cushing syndrome (10,11). Germline PRKAR1A-inactivating mutations were found in both patients with isolated PPNAD (5) and those with Carney complex (CNC) (11), a multiple neoplasia syndrome with PPNAD as its main endocrine manifestation (12).…”

“…The PRKAR1A gene was found to be responsible for most cases of primary pigmented adrenocortical disease (PPNAD), a rare cause of ACTHindependent Cushing syndrome (10,11). Germline PRKAR1A-inactivating mutations were found in both patients with isolated PPNAD (5) and those with Carney complex (CNC) (11), a multiple neoplasia syndrome with PPNAD as its main endocrine manifestation (12). We have also observed somatic PRKAR1A mutations and R1A down-regulation in a subset of sporadic-secreting ACA (13).…”

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).…”

Tumores adrenocorticais na criança: da abordagem clínica à avaliação molecular

“…Em cerca de 60% dos pacientes com CC, uma mutação foi identi-ficada no gene da proteína kinase dependente de cAMP (PRKAR1A), principal mediador do sistema cAMP, diretamente envolvido na via de sinalização de ACTH. Mutações no gene PRKAR1A, localizado no 17q22-24, foram identificadas em adenomas adrenais, porém não em carcinomas adrenais; por outro lado, LOH dessa região foi encontrada em 23% dos adenomas e em 53% dos carcinomas adrenocorticais (37,38).…”