Identification of a Novel Genetic Locus for Familial Cardiac Myxomas and Carney Complex

Casey, Mairead; Mah, Caroline S.; Merliss, Andrew; Kirschner, Lawrence S.; Taymans, Susan E.; Denio, A E; Korf, Bruce R.; Irvine, Alan D.; Hughes, Alison; Carney, J. Aidan; Stratakis, Constantine A.; Basson, Craig T.

doi:10.1161/01.cir.98.23.2560

Cited by 199 publications

(119 citation statements)

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Section: Methodsmentioning

confidence: 99%

“…Informed consent was obtained as required by Weill Medical College's institutional review board, and participants were evaluated as described (10). 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).…”

Section: Methodsmentioning

confidence: 99%

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

Veugelers

Wilkes

Burton

et al. 2004

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

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144

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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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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

Veugelers

Wilkes

Burton

et al. 2004

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

Self Cite

144

122

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“…This finding was then confirmed in another large kindred that had a number of recombinant genotypes with the first locus (101). Genetic heterogeneity was confirmed in this syndrome when a second locus on 17q22-24 was identified (86). So far, no chromosome 17 abnormalities have been seen in tumors from patients with the complex (unpublished information).…”

Section: Carney Complexmentioning

confidence: 89%

“…The genetic defects responsible for the lentiginosis syndromes remain unknown. Two genetic loci have been determined for Carney complex by linkage analysis of polymorphic markers from likely areas of the genome (10,86). Initially, positive lod scores were obtained for nine markers on the short arm of chromosome 2, identifying an approximately 4 centiMorgan (cM)-long area in the cytogenetic band 2p16 (CNC locus), which was likely to contain the gene(s) responsible for the complex (87) (Figure 6a).…”

Section: Carney Complexmentioning

confidence: 99%

Genetics of Carney complex and related familial lentiginoses, and other multiple tumor syndromes

Stratakis

2000

Front Biosci

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“…Os somatotrofinomas, geralmente macroadenomas, estão presentes em 10% a 21% dos pacientes portadores do complexo de Carney, podendo estar associados a gigantismo ou acromegalia (43). Embora não se conheça o defeito genético responsável por esta síndrome, o complexo de Carney foi mapeado por análise de "linkage" aos cromossomos 2p15-16 e 17q 23-24 em diferentes famílias (44,45). Adicionalmente, existem evidências recentes de que a região 2p 16 pode estar envolvida na patogênese do acro-gigantismo familiar isolado (46).…”

Section: Somatotrofinomas De Ocorrência Familiarunclassified

Tumorigênese hipofisária

Bronstein

Melmed²

2005

Arq Bras Endocrinol Metab

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RESUMOOs tumores hipofisários, adenomas na sua quase totalidade, representam de 10% a 15% das neoplasias intracranianas (1) e são encontrados em até 27% de autópsias não selecionadas, como achado incidental (2). Morfologicamente são classificados em microadenomas (< 1cm de diâmetro) e macroadenomas, que podem ser circunscritos, invasivos e/ou expansivos. Do ponto de vista funcional, são divididos em adenomas secretores (de PRL, GH, ACTH, TSH, LH e FSH, podendo co-secretar dois ou mais hormônios) e clinicamente não secretores ou "não funcionantes". O diagnóstico é feito pelo fenótipo da hipersecreção (acromegalia, Cushing etc.) e, nos macroadenomas com efeito de massa, por hipopituitarismo e/ou distúrbios neurológicos, onde predominam as queixas visuais e cefaléia. Quanto aos mecanismos de tumorigênese hipofisária, a disputa entre causa primária hipotalâmica versus hipofisária ganhou força a favor da segunda graças às evidên-cias da monoclonalidade dos tumores, juntamente com outros argumentos como a ausência de tecido hiperplásico circundando o adenoma cirurgicamente removido e a relativa independência do controle hipotalâmico. No entanto, admite-se que um papel permissivo do hipotálamo é importante para a progressão tumoral. Muitos mecanismos moleculares envolvidos na tumorigenese hipofisária já foram desvendados, incluindo oncogenes, genes supressores tumorais e fatores de crescimento, e serão descritos neste artigo de revisão. ABSTRACT Pituitary Tumorigenesis.Pituitary adenomas, almost invariably adenomas, account for 10% to 15% of all intracranial neoplasms and are incidentally detected in up to 27% of non selected autopsies. They are morphologically classified as microadenomas (diameter < 1cm) or macroadenomas, which can be enclosed, invasive and/or expansive. Functionally, they are classified as secreting adenomas (PRL, GH, ACTH, TSH, LH, and FSH, and those cosecreting two or more hormones), and clinically non secreting or "non functioning" tumors. Diagnosis is based on the hypersecretion phenotype (acromegaly, Cushing, etc), and on mass effect of macroadenomas leading to neurological disturbances, mainly visual complaints and headache. Pituitary tumorigenesis mechanisms include those of primary hypothalamic versus pituitary origin, the latter is supported by evidence of pituitary adenoma monoclonality, as well as the absence of hyperplastic tissue surrounding the surgically removed tumor, and the relative independence of tumor hypothalamic control. Nevertheless, a permissive role of the hypothalamus on tumor progression is also postulated. Several molecular mechanisms involved in pituitary tumorigenesis have been unraveled including oncogenes, tumor suppressor genes and growth factors involved in neoplastic development, and will be

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Identification of a Novel Genetic Locus for Familial Cardiac Myxomas and Carney Complex

Abstract: The ultimate identification and analysis of the Carney complex disease gene at this human chromosome 17q2 locus will facilitate diagnosis and treatment of cardiac myxomas and will foster new concepts in regulation of cardiac cell growth and differentiation.

Cited by 199 publications

References 21 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

Genetics of Carney complex and related familial lentiginoses, and other multiple tumor syndromes

Tumorigênese hipofisária

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