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

• Published in: Nature genetics Vol. 26; no. 1; pp. 89 - 92
• Main Authors: Stratakis, Constantine A, Kirschner, Lawrence S, Carney, J. Aidan, Pack, Svetlana D, Taymans, Susan E, Giatzakis, Christoforos, C ho, Yee Sook, Cho-Chung, Yoon S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.09.2000
• Subjects: Acromegaly - genetics; Alleles; Biological and medical sciences; Blotting, Western; Cancer; Chromatography, High Pressure Liquid; Chromosomes, Human, Pair 17; Chromosomes, Human, Pair 2; Complications and side effects; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; Diagnosis; DNA Mutational Analysis; DNA, Complementary - metabolism; Endocrine Gland Neoplasms - genetics; Endocrinopathies; Exons; Expressed Sequence Tags; Family Health; Female; Gene mutations; General aspects. Associated endocrine diseases. Endocrine paraneoplasic syndromes; Genotype; Germ-Line Mutation; Homozygote; Humans; Introns; Loss of Heterozygosity; Male; Medical sciences; Microsatellite Repeats; Molecular Sequence Data; Mutation; Myxoma - genetics; Neoplasms - genetics; Neurilemmoma - genetics; Nucleic Acid Heteroduplexes; Pedigree; Phenotype; Physiological aspects; Polymorphism, Genetic; Protein kinases; Risk factors; Skin Pigmentation - genetics; United States; Endocrinopathy; Human; Enzyme; Family study; Transferases; Regulatory subunit; Genetic disease; Protein kinase; Multiple endocrine neoplasia; Loss of heterozygosity; Tumor; Mutation; Tumor suppressor gene
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/79238

Carney complex (CNC) is a multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumours and psammomatous melanotic schwannomas. CNC is inherited as an autosomal dominant 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 and other features, such as paradoxical responses to endocrine signals, genes implicated in cyclic nucleotide-dependent signalling have been considered candidates for causing CNC (ref. 10). In CNC families mapping to 17q, we detected loss of heterozygosity (LOH) in the vicinity of the gene (PRKAR1A) encoding protein kinase A regulatory subunit 1-α (RIα), including a polymorphic site within its 5′ region. We subsequently identified three unrelated kindreds with an identical mutation in the coding region of PRKAR1A. Analysis of additional cases revealed the same mutation in a sporadic case of CNC, and different mutations in three other families, including one with isolated inherited cardiac myxomas. Analysis of PKA activity in CNC tumours demonstrated a decreased basal activity, but an increase in cAMP-stimulated activity compared with non-CNC tumours. We conclude that germline mutations in PRKAR1A, an apparent tumour-suppressor gene, are responsible for the CNC phenotype in a subset of patients with this disease.