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Clinical and molecular genetics of Carney complex

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Abstract

Carney complex (CNC) is a multiple endocrine neoplasia (MEN) syndrome characterized by lentigines, cardiac myxomas and tumors, including primary pigmented adrenocortical disease (PPNAD). In the present report we review the main clinical manifestations of this disorder. We also discuss some of the newest molecular information regarding CNC. The complex has been mapped to 2p16 and 17q22–24, and a third locus appears likely. The gene coding for the protein kinase A (PKA) type I-a regulatory subunit (RIa), PRKAR1A, had been mapped to 17q. Cloning of the PRKAR1A genomic structure and its sequencing showed mutations in CNC patients. So far, among 57 kindreds, PRKAR1A mutations have been found in 28. In almost all the mutations, the sequence change is predicted to lead to a premature stop codon; 1 mutation altered the initiator ATG codon. Analysis of mRNA transcripts in patient lymphocytes treated with cycloheximide showed that mutant mRNAs containing a premature stop codon were degraded, due to nonsense-mediated mRNA decay—the predicted mtPRKAR1A protein products were absent in these cells. In CNC tumors, PKA activity showed increased stimulation by cAMP, whereas PKA activity ratio was decreased. To date, mutations in the PRKAR1A gene have been described in CNC patients and in some sporadic endocrine tumors. LOH of the normal allele and increased PKA activity in response to cAMP are found in these tumors, suggesting that normal PRKAR1A (largely responsible for PKA type I activity) is implicated more widely in endocrine tumorigenesis. CNC is the first human disease caused by mutations of one of the subunits of the PKA holoenzyme, a critical component of numerous cellular signaling systems.

Introduction

Carney complex (CNC) (OMIM 160980) [1] is a multiple neoplasia syndrome, inherited in an autosomal dominant manner, characterized by lentigines, cardiac myxomas and numerous endocrine and other tumors; among the former the most common is primary pigmented nodular adrenocortical disease (PPNAD) [2]. Most cases are familial [3], but sporadic cases have also been reported [4], [5]. Sporadic cases were previously described under the acronyms of LAMB (lentigines, atrial myxomas and blue nevi) [6] or NAME (nevi, atrial myxomas and phelides) [7]; it appears that most of these patients actually have CNC [3], [8].

CNC has been considered a form of multiple endocrine neoplasia (MEN), because CNC patients frequently present with more than two endocrine tumors [9]. Two genetic loci have been identified for CNC, on chromosome 2 in band p16 [10] and chromosome 17 in bands q22–24 [11]. This second locus contains the gene encoding the regulatory subunit α of the protein kinase A (PRKAR1A) which has recently been shown to be mutated in almost half of the CNC patients [12], [13].

The diagnostic criteria for CNC have been reviewed recently [3]; they can be summarized as follows: a patient is affected if the presence of two main components of the condition are proven by histology and/or biochemical testing or imaging. These components are: spotty skin pigmentation, cutaneous or mucosal myxoma, cardiac myxoma, breast myxoma, PPNAD, growth-hormone (GH)-producing adenoma, large-cell calcifying Sertoli cell tumor (LCCSCT), thyroid carcinoma, psammomatous melanotic schawannoma, blue nevus, breast ductal adenoma, and osteochondromyxoma. The diagnosis may also be made if one of these manifestations is present and a familial pattern or inactivating mutations of the PRKAR1A gene are also shown. The diagnostic criteria for the disorder, as those were recently published, are listed in Table 1.

Section snippets

Skin manifestations

Skin lesions are the most consistent finding in CNC. Lentigines (small, brown to black, non or slightly elevated, round or irregular) and blue nevi (large, blue to black, domed lesion) observed primarily in facies, eyelids, ears, and borders of the lips are the most frequent component of the complex [3] (Fig. 1). It has been observed in half of the patients before the evolution of the other conditions [14]. Other frequent skin lesions are multiple cutaneous myxomas. These usually present as

Genetic heterogeneity in CNC

As mentioned above, linkage analysis in CNC families has shown at least two main loci for candidate genes. The 2p16 locus was identified first [10], but the gene responsible for CNC in that region remains unknown. The most closely linked region on chromosome 2 centers around locus CA2/D2S123; there have not been significant changes from the genetic map that was originally published by Stratakis et al. [10]. Unfortunately, a gap exists in the available maps of chromosome 2 centromeric to this

Mutations of the PRKAR1A gene in CNC

Because of the similarities between CNC and McCune–Albright syndrome, activating mutations of the Gsα gene [38], or genes related to this pathway were long considered possible candidates for CNC [39]. Indeed, the PRKAR1A gene encodes the regulatory subunit 1-α of the protein kinase A, the main mediator of cAMP signaling in mammals [40]. The four genes that code for the various PKA regulatory subunits are grouped into two types, type I and type II. These define the two main isoforms of PKA,

Summary

Carney complex is a recently identified multiple neoplasia syndrome. Its study offers the opportunity to link molecularly an endocrine developmental disorder with cancer genetics. Indeed, the first gene identified to be mutated in CNC, PRKAR1A, offers a glimpse of what might ensue in these investigations. It regulates cAMP signaling, appears to be functioning as a tumor suppressor gene in some cases, but has also complex developmental effects and its inhibition in cancer cell lines in the past

Acknowledgements

We thank Mrs. Caroline Sandrini (Indaial, Santa Catarina, Brazil) for preparing the artwork for this article.

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