Genetics of Carney Complex

Abstract

Carney complex (CNC) is an autosomal dominant multiple neoplasia and lentiginosis syndrome characterised by spotty skin lesions, cardiac and other myxomas and different types of endocrine tumours. The PRKAR1A gene, which codes for the regulatory subunit type 1‐alpha of the cyclic adenosine monophosphate (cAMP)‐activated protein kinase A, is responsible for more than two‐thirds of the cases of CNC described to date. Currently, more than 120 different disease‐causing PRKAR1A sequence variants have been reported. Other involved genes for adrenal hyperplasias include phosphodiesterases PDE11A and PDE8B. Additional genes are likely to be identified that may expand our understanding on the pathophysiology of the cAMP signalling pathway and how genetic defects cause CNC and its individual components such as adrenal tumours.

Key Concepts:

  • Inactivating PRKAR1A mutations cause CNC because PRKAR1A haploinsufficiency leads to uncontrolled PKA activity.

  • The majority (∼80%) of PRKAR1A mutations causing CNC result in an early stop codon generation and degradation of the mutant RNA through nonsense‐mediated RNA decay (NMD).

  • Recently, novel types of PRKAR1A mutations have been described: large gene rearrangements and small indels resulting in an elongated protein through downstream shift of the stop codon.

  • The penetrance of PRKAR1A mutations is more than 95% by the age of 50 years.

  • PDE11A and PDE8B genetic defects contribute to the CNC phenotype, but they may also independently cause forms of adrenal hyperplasia, mainly isolated micronodular adrenocortical disease (iMAD).

  • Genotype–phenotype correlation is limited, but there are certain mutations that cause more frequently certain endocrine manifestations such as isolated Cushing syndrome.

  • The use of new genomic techniques has led to the identification of new genetic defects in PRKAR1A and related genes in CNC.

Keywords: Carney complex; PRKAR1A; mutations; PDE11A; PDE8B; genotype‐phenotype correlations

Figure 1.

Molecular mechanisms by which mutations in PRKAR1A lead to CNC: defective protein with impaired ability to bind the catalytic subunit and/or cAMP or reduced levels of wild‐type RIα (all the mutations leading to either NMD‐ or proteosome‐mediated degradation).

Figure 2.

Mutation detection rate among CNC patients: (a) soon after the identification of PRKAR1A as a gene responsible for the disease phenotype, (b) after the fusion of the major databases and (c) currently. The mutation detection rate has increased from 50% (2000) to more than 70% (2012) and in addition, genetic defects in PDE11A and PDE8B were identified in patients with Cushing syndrome caused by micronodular hyperplasia.

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Further Reading

Lewis R (2011) Human Genetics: Concepts and Applications, 10th edn. Columbus, OH, USA: McGraw‐Hill Companies, Inc.

Weiss R and Refetoff S (eds) (2010) Genetic Diagnosis of Endocrine Disorders, 1st edn. Waltham, MA, USA: Academic Press.

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Horvath, Anelia, and Stratakis, Constantine A(Mar 2013) Genetics of Carney Complex. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.A0024305]