Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex

Carney complex (CNC) is a multiple neoplasia syndrome characterized by spot ty skin pigmentation, cardiac and other myxomas, endocrine tumours and psam momatous melanotic schwannomas(1-5). CNC is inherited as an autosomal domin ant trait and the genes responsible have been mapped to 2p16 and 17q22-24 ( refs 6,7). Because of its similarities to the McCune-Albright syndrome(5,8) and other features, such as paradoxical responses to endocrine signals(9), genes implicated in cyclic nucleotide-dependent signalling have been consi dered candidates for causing CNC (ref. 10). In CNC families mapping to 17q. we detected loss of heterozygosity (LOH) in the vicinity of the gene (PRKA R1A) encoding protein kinase A regulatory subunit 1-alpha (Rl alpha), inclu ding a polymorphic site within its 5' region. We subsequently identified th ree unrelated kindreds with an identical mutation in the coding region of P RKAR1A. Analysis of additional cases revealed the same mutation in a sporad ic case of CNC, and different mutations in three other families, including one with isolated inherited cardiac myxomas. Analysis of PKA activity in CN C tumours demonstrated a decreased basal activity, but an increase in cAMP- stimulated activity compared with non-CNC tumours, We conclude that germlin e mutations in PRKAR1A, an apparent tumour-suppressor gene, are responsible for the CNC phenotype in a subset of patients with this disease.