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

Nature Genetics volume 26, pages 89–92 (2000)Cite this article

Abstract

Carney complex (CNC) is a multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumours and psammomatous melanotic schwannomas1,2,3,4,5. 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 syndrome5,8 and other features, such as paradoxical responses to endocrine signals9, 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.

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Figure 1: Pedigree and chromosome 17 genotyping of family CAR20.
Figure 2: Loss-of-heterozygosity analysis of chromosome 17 near PRKAR1A.
Figure 3: Detection of a frameshift mutation in CAR01 in PRKAR1A exon 4B.
Figure 4: PKA activity and expression of PRKAR1A in CNC tumours and cell lines.

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Acknowledgements

We thank the patients and their families for their support and patience; the physicians who have sent us patients and patient samples over the years, particularly R. Pyeritz, S. Mendoza, K. Tuckerman, J. Toppari and A. Reza; M. Schoenberg-Fejzo and L. Peltonen for discussions on the status of the chromosome 17 genetic and physical maps; S. Marx for discussions on multiple endocrine neoplasias; R. Alexander, S. Libutti, D. Burtlet and E. Oldfield for surgical services; C. Basson for collaboration on the first chromosome 17 linkage study; J. Monbo and L. Goldman for technical assistance; C. Bondy and I. Dawid for critical review of the data; and the nursing and other support staff on the 8W and 9W inpatient wards at the NIH for their support of our research studies and their help in the management of patients with Carney complex.

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Authors and Affiliations

  1. Unit on Genetics & Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development , Bethesda, Maryland, USA

    Lawrence S. Kirschner, Svetlana D. Pack, Susan E. Taymans, Christoforos Giatzakis & Constantine A. Stratakis

  2. Laboratory of Pathology, National Cancer Institute , Bethesda, Maryland, USA

    Svetlana D. Pack

  3. Cellular Biochemistry Section, Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

    Yee Sook Cho & Yoon S. Cho-Chung

  4. Department of Laboratory Medicine and Pathology, Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA

    J. Aidan Carney

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  1. Lawrence S. Kirschner
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Correspondence to Constantine A. Stratakis.

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Kirschner, L., Carney, J., Pack, S. et al. Mutations of the gene encoding the protein kinase A type I-α regulatory subunit in patients with the Carney complex. Nat Genet 26, 89–92 (2000). https://doi.org/10.1038/79238

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