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

ABSTRACT: 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 1alpha 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.

SUBMITTER: Veugelers M

PROVIDER: S-EPMC521100 | biostudies-literature | 2004 Sep

REPOSITORIES: biostudies-literature

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

Veugelers Mark M Wilkes David D Burton Kimberly K McDermott Deborah A DA Song Yan Y Goldstein Marsha M MM La Perle Krista K Vaughan Carl J CJ O'Hagan Art A Bennett Kenneth R KR Meyer Beat J BJ Legius Eric E Karttunen Mervi M Norio Reijo R Kaariainen Helena H Lavyne Michael M Neau Jean-Philippe JP Richter Gert G Kirali Kaan K Farnsworth Alan A Stapleton Karen K Morelli Peter P Takanashi Yoshinori Y Bamforth John-Steven JS Eitelberger Franz F Noszian Irene I Manfroi Waldimiro W Powers James J Mochizuki Yoshihiko Y Imai Tsuneo T Ko Gary T C GT Driscoll Deborah A DA Goldmuntz Elizabeth E Edelberg Jay M JM Collins Amanda A Eccles Diana D Irvine Alan D AD McKnight G Stanley GS Basson Craig T CT

Proceedings of the National Academy of Sciences of the United States of America 20040915 39

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 1alpha 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 consequen ...[more]

PMID: 15371594

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Project description:ContextMost tumors in Carney complex (CNC) are benign, including primary pigmented nodular adrenocortical disease (PPNAD), the main endocrine tumor in CNC. Adrenocortical cancer (AC) has never been observed in the syndrome. Herein, we describe a large Azorean family with CNC caused by a point mutation in the PRKAR1A gene coding for type 1-α (RIα) regulatory subunit of the cAMP-dependent protein kinase A, in which the index patient presented with AC.ObjectiveWe studied the genotype-phenotype correlation in CNC.Design and settingWe reported on case series and in vitro testing of the PRKAR1A mutation in a tertiary care referral center.PatientsTwenty-two members of a family were investigated for Cushing syndrome and other CNC components; their DNA was sequenced for PRKAR1A mutations.ResultsCushing syndrome due to PPNAD occurred in four patients, including the proposita who presented with AC and three who had Cushing syndrome and/or PPNAD. Lentigines were found in six additional patients who did not have PPNAD. A base substitution (c.439A>G/p.S147G) in PRKAR1A was identified in the proposita, in the three others with PPNAD, in the proposita's twin daughters who had lentigines but no evidence of hypercortisolism, and in five other family members, including one without lentigines or evidence of hypercortisolism. Unlike in other RIα defects, loss of heterozygosity was not observed in AC. The S147G mutation was compared to other expressed PRKAR1A mutations; it led to decreased cAMP and catalytic subunit binding by RIα and increased protein kinase A activity in vitro.ConclusionsIn a large family with CNC, one amino acid substitution caused a spectrum of adrenal disease that ranged from lack of manifestations to cancer. PPNAD and AC were the only manifestations of CNC in these patients, in addition to lentigines. These data have implications for counseling patients with CNC and are significant in documenting the first case of AC in the context of PPNAD.

Dataset Information

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

Publications

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

Similar Datasets

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