Mutations in the protein kinase A R1α regulatory subunit cause familial cardiac myxomas and Carney complex

Casey, Mairead; Vaughan, Carl J.; He, Jié; Hatcher, Cathy J.; Winter, Jordan M.; Weremowicz, Stanislawa; Montgomery, Kate; Kucherlapati, Raju; Morton, Cynthia C.; Basson, Craig T.

doi:10.1172/jci10841

“…Phlebotomy was performed, and lymphoblastoid cell lines were established (10). Genomic DNA was isolated, and genotyping and mutational analyses of PRKAR1A coding exons were performed by using denaturing HPLC and automated sequencing (7,11). PRKAR1A cDNA was reverse-transcribed from RNA (RNeasy, Qiagen, Valencia, CA) with Superscript (Invitrogen) and PCR-amplified (30 s at 94°C, 30 s at 55°C, and 60 s at 72°C) ϫ 35 cycles.…”

Section: Methodsmentioning

confidence: 99%

“…Lysates from cultured cells or murine tissues were analyzed by Western blot with monoclonal anti-R1␣ antibody (BD Transduction Laboratories, San Diego; ref. 7). Recombinant R1␣ isoforms were expressed in COS-7 cells by Lipofectamine (BRL) transfection with pcDNA3.1 plasmids containing PRKAR1A cDNAs 3Ј to cassettes encoding a FLAG tag (DYKDDDDK) and a linker (SGA).…”

Section: Methodsmentioning

confidence: 99%

“…Mutations in the chromosome 17q24 PRKAR1A gene encoding the R1␣ regulatory subunit of cAMP-dependent protein kinase A (PKA) cause CNC in some kindreds (7,8). PRKAR1A mutant mRNAs were predicted to be degraded via nonsense-mediated decay (NMD), and PRKAR1A haploinsufficiency was hypothesized to cause CNC (7)(8)(9).…”

mentioning

confidence: 99%

“…Mutations in the chromosome 17q24 PRKAR1A gene encoding the R1␣ regulatory subunit of cAMP-dependent protein kinase A (PKA) cause CNC in some kindreds (7,8). PRKAR1A mutant mRNAs were predicted to be degraded via nonsense-mediated decay (NMD), and PRKAR1A haploinsufficiency was hypothesized to cause CNC (7)(8)(9). Some, but not all, CNC tumors showed PRKAR1A loss of heterozygosity (LOH) and dysregulated PKA activity (8), but contributions of LOH and PKA activity to CNC tumorigenesis have remained controversial.…”

mentioning

confidence: 99%

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Comparative PRKAR1A genotype–phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice

Veugelers

¹

,

Wilkes

²

,

Burton

³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Carney complex (CNC) is a familial multiple neoplasia syndrome characterized by cardiac and extracardiac myxomas in the setting of spotty skin pigmentation and endocrinopathy. We previously identified PRKAR1A (regulatory subunit 1α of protein kinase A) mutations in CNC. Mutational analyses of the PRKAR1A gene in 51 unrelated CNC probands now detect mutations in 65%. All mutations, except for one unique missense mutation, lead to PRKAR1A haploinsufficiency. Therefore, we studied the consequences of prkar1a haploinsufficiency in mice. Although we did not observe cardiac myxomas or altered pigmentation in prkar1a +/– mice, we did observe some phenotypes similar to CNC, including altered heart rate variability. Moreover, prkar1a +/– mice exhibited a marked propensity for extracardiac tumorigenesis. They developed sarcomas and hepatocellular carcinomas. Sarcomas were frequently associated with myxomatous differentiation. Tumors from prkar1a +/– mice did not exhibit prkar1a loss of heterozygosity. Thus, we conclude that although PRKAR1A haploinsufficiency does predispose to tumorigenesis, distinct secondary genetic events are required for tumor formation.

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“…Haploinsufficiency of Prkar1a with consequent imbalance in the ratio between PRKAR1a to PRKARIIb (R2beta regulatory subunit of PKA) was proposed to cause tumour development in some cases. 6 Increased PKA activity increases extracellular receptor kinase (ERK1/2) mitogen-activated protein kinase (MAPK) pathway signalling. 7,8 This causes an increase in the levels of the transcription factors c-MYC and c-FOS.…”

mentioning

confidence: 99%

Loss of Prkar1a leads to Bcl-2 family protein induction and cachexia in mice

Gangoda

¹

,

Doerflinger

²

,

Srivastava

³

et al. 2014

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Loss of function mutations in the Prkar1a gene are the cause of most cases of Carney complex disorder. Defects in Prkar1a are thought to cause hyper-activation of PKA signalling, which drives neoplastic transformation, and Prkar1a is therefore considered to be a tumour suppressor. Here we show that loss of Prkar1a in genetically modified mice caused transcriptional activation of several proapoptotic Bcl-2 family members and thereby caused cell death. Interestingly, combined loss of Bim and Prkar1a increased colony formation of fibroblasts in culture and promoted their growth as tumours in immune-deficient mice. Apart from inducing apoptosis, systemic deletion of Prkar1a caused cachexia with muscle loss, macrophage activation and increased lipolysis as well as serum triglyceride levels. Loss of single allele of Prkar1a did not enhance tumour development in a skin cancer model, but surprisingly, when combined with the loss of Bim, caused a significant delay in tumorigenesis and this was associated with upregulation of other BH3-only proteins, PUMA and NOXA. These results show that loss of Prkar1a can only promote tumorigenesis when Prkar1a-mediated apoptosis is somehow countered.

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Genetics of Carney Complex

Horvath

¹

,

Stratakis

²

2013

Encyclopedia of Life Sciences

0

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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.

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Mutations in the protein kinase A R1α regulatory subunit cause familial cardiac myxomas and Carney complex

Cited by 252 publications

References 40 publications

Comparative PRKAR1A genotype–phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice

Comparative PRKAR1A genotype–phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice

Loss of Prkar1a leads to Bcl-2 family protein induction and cachexia in mice

Genetics of Carney Complex

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