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

Carney complex (CNC) is an autosomal dominant multiple neoplasia syndrome, which has been linked to loci on 2p16 and 17q22-24. We recently reported th at PRKAR1A, which codes for the type 1A regulatory subunit of protein kinas e A (PKA), is a tumor suppressor gene on chromosome 17 that is mutated in s ome CNC families. To evaluate the spectrum of PRKAR1A mutations, we identif ied its genomic structure and screened for mutations in 54 CNC kindreds (34 families and 20 patients with sporadic disease). Fourteen families were in formative for linkage analysis: four of four families that mapped to 17q ha d PRKAR1A mutations, whereas there were no mutations found in seven familie s 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-informat ive families and 7 of 20 sporadic cases. Altogether, 15 distinct PRKAR1A mu tations 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 altere d the initiator ATG codon. Mutant mRNAs containing a premature stop codon w ere unstable, as a result of nonsense-mediated mRNA decay. Accordingly, the predicted truncated PRKAR1A protein products were absent in these cells. W e conclude that (i) genetic heterogeneity exists in CNC; and (ii) all of th e 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 holoen zyme, a critical component of cellular signaling.