Mutations and polymorphisms in the gene encoding regulatory subunit type 1-alpha of protein kinase A (PRKAR1A): an update

Authors

  • Anélia Horvath,

    1. Section on Endocrinology and Genetics, Program in Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, Maryland
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  • Jérôme Bertherat,

    1. INSERM U567, CNRS UMR8104, Institut Cochin, Endocrinology, Metabolism & Cancer Department, Paris, France
    2. Université Paris-Descartes, Paris, France
    3. Assistance Publique-Hôpitaux de Paris, Department of Endocrinology, Hôpital Cochin, Paris, France
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  • Lionel Groussin,

    1. INSERM U567, CNRS UMR8104, Institut Cochin, Endocrinology, Metabolism & Cancer Department, Paris, France
    2. Université Paris-Descartes, Paris, France
    3. Assistance Publique-Hôpitaux de Paris, Department of Endocrinology, Hôpital Cochin, Paris, France
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  • Marine Guillaud-Bataille,

    1. INSERM U567, CNRS UMR8104, Institut Cochin, Endocrinology, Metabolism & Cancer Department, Paris, France
    2. Assistance Publique-Hôpitaux de Paris, Department of Biostatistics, Hôpital Cochin, Paris, France
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  • Kitman Tsang,

    1. Section on Endocrinology and Genetics, Program in Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, Maryland
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  • Laure Cazabat,

    1. INSERM U567, CNRS UMR8104, Institut Cochin, Endocrinology, Metabolism & Cancer Department, Paris, France
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  • Rosella Libé,

    1. INSERM U567, CNRS UMR8104, Institut Cochin, Endocrinology, Metabolism & Cancer Department, Paris, France
    2. Université Paris-Descartes, Paris, France
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  • Elaine Remmers,

    1. Genetics and Genomics Branch, NIAMS, Bethesda, Maryland
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  • Fernande René-Corail,

    1. INSERM U567, CNRS UMR8104, Institut Cochin, Endocrinology, Metabolism & Cancer Department, Paris, France
    2. Université Paris-Descartes, Paris, France
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  • Fabio Rueda Faucz,

    1. Section on Endocrinology and Genetics, Program in Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, Maryland
    2. Laboratory of Molecular Genetics, Pontificia Universidade Catolica do Parana, Curitiba, Brazil
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  • Eric Clauser,

    1. INSERM U567, CNRS UMR8104, Institut Cochin, Endocrinology, Metabolism & Cancer Department, Paris, France
    2. Assistance Publique-Hôpitaux de Paris, Department of Biostatistics, Hôpital Cochin, Paris, France
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  • Alain Calender,

    1. Unit on Genetics and Endocrine Tumors, CNRS UMR 5201, Claude Bernard University and CHU Lyon, Lyon, France
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  • Xavier Bertagna,

    1. INSERM U567, CNRS UMR8104, Institut Cochin, Endocrinology, Metabolism & Cancer Department, Paris, France
    2. Université Paris-Descartes, Paris, France
    3. Assistance Publique-Hôpitaux de Paris, Department of Endocrinology, Hôpital Cochin, Paris, France
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  • J. Aidan Carney,

    1. Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, Ohio State University, Columbus, Ohio
    2. Department of Laboratory Medicine and Pathology (emeritus member), Mayo Clinic, Rochester, Minnesota
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  • Constantine A. Stratakis

    Corresponding author
    1. Section on Endocrinology and Genetics, Program in Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, Maryland
    • Section on Endocrinology & Genetics, PDEGEN, NICHD, NIH, Building 10, CRC, Room I-3330, 10 Center Dr., MSC 1103, Bethesda, MD 20892
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  • This article is a US Government work, and, as such, is in the public domain in the United States of America.

  • Communicated by Jurgen Horst

Abstract

PRKAR1A encodes the regulatory subunit type 1-alpha (RIα) of the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA). Inactivating PRKAR1A mutations are known to be responsible for the multiple neoplasia and lentiginosis syndrome Carney complex (CNC). To date, at least 117 pathogenic variants in PRKAR1A have been identified (online database: http://prkar1a.nichd.nih.gov). The majority are subject to nonsense mediated mRNA decay (NMD), leading to RIα haploinsufficiency and, as a result, activated cAMP signaling. Recently, it became apparent that CNC may be caused not only by RIα haploinsufficiency, but also by the expression of altered RIα protein, as proven by analysis of expressed mutations in the gene, consisting of aminoacid substitutions and in-frame genetic alterations. In addition, a new subgroup of mutations that potentially escape NMD and result in CNC through altered (rather than missing) protein has been analyzed—these are frame-shifts in the 3′ end of the coding sequence that shift the stop codon downstream of the normal one. The mutation detection rate in CNC patients is recently estimated at above 60%; PRKAR1A mutation-negative CNC patients are characterized by significant phenotypic heterogeneity. In this report, we present a comprehensive analysis of all presently known PRKAR1A sequence variations and discuss their molecular context and clinical phenotype. Hum Mutat 31:369–379, 2010. Published 2010 Wiley-Liss, Inc.

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