Mutations in Regulatory Subunit Type 1A of Cyclic Adenosine 5′-Monophosphate-Dependent Protein Kinase (<i>PRKAR1A</i>): Phenotype Analysis in 353 Patients and 80 Different Genotypes

Bertherat, Jérôme; Horvath, Anélia; Groussin, Lionel; Grabar, Sophie; Boikos, Sosipatros A.; Cazabat, Laure; Libé, R.; René-Corail, Fernande; Stergiopoulos, Sotirios; Bourdeau, Isabelle; Bei, Thalia; Clauser, Éric; Calender, Alain; Kirschner, Lawrence S.; Bertagna, Xavier; Carney, J. Aidan; Stratakis, Constantine A.

doi:10.1210/jc.2008-2333

Cited by 398 publications

(484 citation statements)

References 36 publications

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“…In a mouse model of inherited tumour syndrome Carney complex (CNC) with defect in the regulatory subunit 1a of PKA, there is evidence that prkar1a þ / À (regulatory subunit 1a of PKA) mice developed HCC, while the PKA activity in these mice remained unchanged 47 . However, in another study, CNC patients with prkar1a mutations have been shown to develop a spectrum of carcinomas but not HCC 48 . These reported studies reveal an opposing role of cAMP/PKA pathway in different cellular contexts.…”

Section: Discussionmentioning

confidence: 91%

PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis

Chan

Sze

et al. 2013

Nat Commun

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Deleted in Liver Cancer 1 (DLC1) is a tumour suppressor that encodes a RhoGTPase-activating protein (RhoGAP) and is frequently inactivated in many human cancers. The RhoGAP activity of DLC1 against Rho signalling is well documented and is strongly associated with the tumour suppressor functions of DLC1. However, the mechanism by which the RhoGAP activity of DLC1 is regulated remains obscure. Here, we report that phosphorylation of DLC1 at Ser549 by cyclic AMP-dependent protein kinase A contributes to enhanced RhoGAP activity and promotes the activation of DLC1, which suppresses hepatoma cell growth, motility and metastasis in both in vitro and in vivo models. Intriguingly, we found that Ser549 phosphorylation induces the dimerization of DLC1 and that inducible dimerization of DLC1 can rescue the tumour suppressive and RhoGAP activities of DLC1 containing a Ser549 deletion. Our study establishes a novel regulatory mechanism for DLC1 RhoGAP activity via dimerization induced by protein kinase A signalling.

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Section: Discussionmentioning

confidence: 91%

PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis

Chan

Sze

et al. 2013

Nat Commun

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“…At least 50% of individuals with isolated primary pigmented nodular adrenocortical disease have a PRKAR1A mutation. [18][19][20] Thus, isolated primary pigmented nodular adrenocortical disease is sufficient for referral to genetic consultation. PRKAR1A mutations are found in 71% of individuals with at least two major diagnostic criteria for Carney complex 18 ( Table 3).…”

Section: Acmg Practice Guidelinesmentioning

confidence: 99%

A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment

Hampel

Bennett

Buchanan

et al. 2015

Genetics in Medicine

467

326

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Cancer genetic consultation services include the evaluation of patients' personal and family history for concerning features of hereditary cancer predisposition syndromes, development of a differential diagnosis for one or more possible hereditary cancer syndromes, genetic testing if indicated and available, recommendations for management, cancer surveillance and prevention, and information regarding genetic counseling and genetic testing for at-risk relatives. This counseling is informed by the genetic Cancer genetic consultation is an important aspect of the care of individuals at increased risk of a hereditary cancer syndrome. Yet several patient, clinician, and system-level barriers hinder identification of individuals appropriate for cancer genetics referral. Thus, the purpose of this practice guideline is to present a single set of comprehensive personal and family history criteria to facilitate identification and maximize appropriate referral of at-risk individuals for cancer genetic consultation. To develop this guideline, a literature search for hereditary cancer susceptibility syndromes was conducted using PubMed. In addition, GeneReviews and the National Comprehensive Cancer Network guidelines were reviewed when applicable. When conflicting guidelines were identified, the evidence was ranked as follows: position papers from national and professional organizations ranked highest, followed by consortium guidelines, and then peerreviewed publications from single institutions. The criteria for cancer genetic consultation referral are provided in two formats: (i) tables that list the tumor type along with the criteria that, if met, would warrant a referral for a cancer genetic consultation and (ii) an alphabetical list of the syndromes, including a brief summary of each and the rationale for the referral criteria that were selected. Consider referral for a cancer genetic consultation if your patient or any of their firstdegree relatives meet any of these referral criteria.

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“…CNC is a rare endocrine multi-organ syndrome previously diagnosed in ~750 patients (6). A mutation in the PRKAR1A gene has been identified in more than 70% of the cases, including 80% of those with PPNAD (7,10). PRKAR1A is located at the 17q 24.2-24.3 locus and is composed of 11 exons (6).…”

Section: Discussionmentioning

confidence: 99%

Mutations in Regulatory Subunit Type 1A of Cyclic Adenosine 5′-Monophosphate-Dependent Protein Kinase (PRKAR1A): Phenotype Analysis in 353 Patients and 80 Different Genotypes

Abstract: CNC is genetically and clinically heterogeneous. Certain tumors are more frequent, with specific mutations providing some genotype-phenotype correlation for PRKAR1A mutations.

Cited by 398 publications

References 36 publications

PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis

PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis

A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment

Newly Diagnosed Carney Complex in 3 Young Adults with Primary Adrenal Cushing Syndrome – A Case Series and Review of the Literature

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